Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

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YPHRS 2837 1–16

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Contents lists available at ScienceDirect

Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

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Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

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Vikas Dutt a , Sanjeev Gupta a , Rajesh Dabur b , Elisha Injeti c , Ashwani Mittal a,∗ a b c

Skeletal Muscle Lab, University College, Kurukshetra University, Kurukshetra, Haryana 136119, India Biochemistry Department, MD University, Rohtak, Haryana 124001, India Pharmaceutical Sciences Department, Cedarville University, OH 45314, USA

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Article history: Received 6 March 2015 Received in revised form 24 May 2015 Accepted 24 May 2015 Available online xxx

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Keywords: Atrophy Cachexia Eicosapentaenoic acid Resveratrol Cox2 inhibitor Histone decetylase inhibitor Phosphodiesterase inhibitor ␤-Adrenoceptor agonists Megestrol acetate Anti-cytokines Chemical compounds studied in this article: EPA (PubChem CID: 446284) ␤-Hydroxy-␤-methylbutyrate (PubChem CID: 69362) Cis-resveratrol (PubChem CID: 1548910) Trans-resveratrol (PubChem CID: 445154) Ghrelin (PubChem CID: 44576256) Celecoxib (PubChem CID: 2662) Meloxicam (PubChem CID: 54677470) Trichostatin A (PubChem CID: 444732) Torbafylline (PubChem CID: 65888) Pentoxifylline (PubChem CID: 4740) Formoterol (PubChem CID: 3410) Clenbuterol (PubChem CID: 2783) Enobosarm (PubChem CID: 11326715) Thalidomide (PubChem CID: 5426) Megestrol acetate (PubChem CID: 11683)

Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1␣, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified. © 2015 Elsevier Ltd. All rights reserved.

Abbreviations: Cox, cyclooxygenase; CREB, cAMP response element binding protein; CACS, cancer-related anorexia and cachexia syndrome; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; DAG, des-acyl ghrelin; ERK, extracellular signal-regulated kinase; EPA, eicosapentaenoic acid; FoxO, forkhead box O; Epac, exchange protein directly activated by cAMP; eIF4G and eIF4E, eukaryotic translation initiation factor 4G and 4E; HAT, histone acetyltransferase; HDAC, histone deacetylase; HETE, hydroxyeicosatetraenoic acid; HMB, ␤-hydroxy-␤-methylbutyrate; LLC, Lewis lung carcinoma; MAC, murine adeno-carcinoma; NY, neuropeptide Y; NF␬B, nuclear factor kappa; PUFA, polyunsaturated fatty acid; PIF, proteolysis-inducing factor; PPAR␥, peroxisome proliferator-activated receptor; PGE, prostaglandin; PDE, phosphodiesterase; PKA, protein kinase A; PTX, pentoxifylline; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; SARM, selective androgen receptor modulator; SOD, superoxide dismutase; TNF␣, tumor necrosis factor; TWEAK, TNF␣ like weak inducer of apoptosis; TLR, toll-like receptor; TPA, 12-0-tetradecanoylphorbol-13-acetetate; TGF␤1, transforming growth factor beta 1; TSA, trichostatin A; CKD, chronic kidney disease; Activin type II receptor, ActRIIB, ActRIIA; Activinlike kinase, ALK4, ALK5; MuRF1, muscle-specific RING-finger 1. ∗ Corresponding author. Tel.: +91 01744 238049; fax: +91 01744 238008. E-mail address: [email protected] (A. Mittal). http://dx.doi.org/10.1016/j.phrs.2015.05.010 1043-6618/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: V. Dutt, et al., Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.05.010

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Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Classification and mechanisms of actions of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Natural compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1.1. Eicosapentanoic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1.2. ␤-Hydroxy-␤-methylbutyrate (HMB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1.3. Resveratrol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1.4. Ghrelin and its receptor agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Enzyme inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.1. Cox2 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.2. Histone decetylase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2.3. PDE inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. ␤-Adrenoceptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.1. Formoterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.2. Clenbuterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4. Anti-cytokines agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.1. Anti-TNF␣ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.2. Thalidomide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5. Other investigational drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.1. Enobosarm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.2. GLPG0492 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.3. OHR/AVR118 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.4. APD209 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.5.5. Anti-myostatin/activin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.6. Miscellaneous agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.6.1. Megestrol acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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1. Introduction

In the current literature, three factors that can initiate loss of 79 skeletal muscle mass have been identified. They are (1) chronic 80 diseases (cachexia) like diabetes, cancer, chronic obstructive pul81 monary disease (COPD), acquired immune deficiency syndrome 82 (AIDS), and renal/cardiac failure, (2) disuse conditions (atrophy) 83 like denervation, immobolization, and microgravity (3) aging 84 (sarcopenia). These factors gradually lead to distinct phenotypic 85 changes in the skeletal muscle by accelerating protein degrada86 tion [1–5]. Muscle wasting and weakness generated in each of 87 these conditions (cachexia, atrophy, and sarcopenia) is a complex 88 and highly regulated phenomenon, characterized by substantial 89 decrease in muscle fiber cross-sectional area, myonuclear number, 90 protein content and muscle strength while increasing in fatigabil91 ity and resistance to insulin [2,6–8]. In addition, it is also associated 92 with an increased risk of death. 93 Beyond a reduced survival rate, wasting is also linked to poor 94 functional status and quality of life. Up to one-third of all can95 cer patients die due to direct consequences of cachexia and 96 not from cancer, while in AIDS, more than 5% weight loss over a period of 4-months are associated with an increased risk of 97 death and opportunistic infections. Studies have revealed that 98 different types of molecular triggers/catabolic players such as 99 myostatin, pro-inflammatory cytokines i.e. tumor necrosis fac100 tor alpha (TNF␣), interleukin-1 beta (IL-1␤), interleukin-6 (IL-6), 101 TNF-like weak inducer of apoptosis (TWEAK), interferon gamma 102 (IFN␥) are involved in muscle wasting under above mentioned 103 clinical settings [7,9,10]. These cytokines on binding to their 104 respective receptor results in activation of the NF␬B, a common 105 transcription factor in most of the protein catabolic pathways 106 Q4 leading to proteolysis in skeletal muscles (Supplementary Fig. 107 1). This makes nuclear factor kappa B (NF␬B) an attractive 108 pharmaceutical target for therapeutic interventions. Other impor109 tant targets include anabolic pathways (phosphatidylinositide 78Q3

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3-kinases/protein kinase B; PI3K/Akt) and five major proteolytic machineries like Ca2+ -dependent calpain, Ca2+ -independent cathepsin L, autophagy, ubiquitin (Ub)–proteasome system and the caspase system [3,11,12]. Caspases are critical not only for muscle atrophy but also for the apoptotic process. The majority of the muscles wasting studies have demonstrated that autophagy system uses lysosomal enzymes (like cathepsin L) for the processing of damaged cellular components [12]. There are some studies which have reported enhanced cathepsin L activity without any change in the level of autophagy related markers under atrophic conditions [13–15]. These studies highlight the possibility of cathepsin L dependent and independent autophagy systems. Moreover, several reports in literature indicate that cathepsin L may be present in extracellular compartment independent to lysosomal fraction which further illustrates the probable special role of this protease during atrophy [16,17]. Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phrs.2015.05.010 In spite of many promising therapeutic targets for treating muscle wasting, not even a single drug is clinically proven to be safe. In this review, we classify nineteen potential drugs (that are in use at laboratory/preclinical level of investigation using different atrophic models) into six categories and then discuss their mechanism of action (Fig. 1). Q5

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2. Classification and mechanisms of actions of drugs

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2.1. Natural compounds

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The mechanisms of action of four natural compounds are discussed in this section. These compounds are (A) eicosapentanoic acid, (B) ␤-hydroxy-␤-methylbutyrate, (C) resveratrol, and (D) ghrelin and its receptor agonists.

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Inhibition Activator Down-regulation Up-regulation Mediated Inhibition

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Fig. 1. Symbols used in the figures.

2.1.1. Eicosapentanoic acid Eicosapentaenoic acid (EPA) is a naturally occurring long-chain Q6 142 polyunsaturated fatty acid (PUFA) of omega-3 (␻-3) family mainly 143 found in deep-sea fish and certain algae. EPA exhibits diverse phar144 macological actions including anti-genotoxic, anti-oxidant and 145 chemo-preventive effects. Numerous studies showed that in can146 cer patients there is a progressive muscle wasting (75% decrease in 147 skeletal muscle protein mass) which makes it a key reason for the 148 cause of cachexia. This is due to up-regulation in the level of various 149 pro-inflammatory cytokines and their mediated activation of skele150 tal muscle specific proteolytic system. One of those systems is the 151 NF␬B-dependent ubiquitin–proteasome pathway which is respon152 sible for degradation of myofibrillar proteins and thus skeletal 153 muscle wasting [18–20]. Studies have shown that EPA suppresses 154 the production of pro-inflammatory cytokines such as IL-1, TNF␣ 155 and IL-6 in cancer induced cachexia [21–23]. EPA also inhibits the 156 NF␬B activation by suppressing IB kinase activity (IKK, an enzyme 157 that phosphorylate I␬B and promotes its degradation). This stops 158 the translocation of NF␬B from cytosol into nucleus and prevents 159 the expression of various components of the proteolytic machinery 160 such as muscle-specific E3 ubiquitin ligase (muscle-specific RING161 finger 1, MuRF1). This process tremendously helps in preserving 162 the skeletal muscle mass [24,25]. 163 In vivo studies have shown that murine adeno-carcinoma-16 164 (MAC16) tumor bearing mice when treated with EPA displayed 165 decreased proteasome activity (i.e. decrease in expression of 166 20S proteasome protein and the p42 regulator) in gastrocne167 mius muscle [26]. EPA also controls the proteolysis-inducing 168 factor (PIF)/15-lipoxygenase (15LOX)/15-hydroxyeicosatetraenoic 169 acid (15HETE)-mediated activation of NF␬B pathway in cancer 170 cachexia. This study shows that EPA down-regulates the protein 171 catabolism process by inhibiting the release of arachidonic acid 172 (AA) from muscle cells in the presence of the PIF and its conver173 sion into 15LOX metabolite i.e. 15HETE. This is the only metabolite 174 formed from arachidonic acid that has the capability of inducing 175 protein degradation through NF␬B/Ub–proteasome system by acti176 vating IKK and protein kinase C (PKC). It can be concluded that 177 EPA regulates the cancer cachexia by targeting the production of 178 15HETE and stabilizing the I␬B/NF␬B complex [27,28]. 179 A large number of studies have shown that carcinoma bear180 ing mice (such as Colon-26 and Lewis lung) can induce cancer 181 cachexia by up-regulating the levels of expression of paired box7 182 (Pax7), which inhibits the myogenin transcription factor thereby 183 blocking the myogenesis program [29–32]. However, EPA treat184 ment in association with endurance exercise for short periods can 185 partially prevent this increase in Pax7 levels in Lewis lung carci186 noma (LLC) bearing mice and thus improving the muscle wasting 187 141

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condition [32]. EPA also stimulates mitochondrial biogenesis by up-regulating peroxisome proliferator-activated receptor gamma coactivator-1␣ (PGC-1␣) protein levels in LLC-bearing mice and carries out fiber-types switching from glycolytic fibers to oxidative fibers which makes the fiber less susceptible to atrophy [32]. EPA administration can also increase the reactive oxygen species (ROS) scavenging activity of superoxide dismutase (SOD), and thus increased the weight gain in pancreatic cancer patients [33]. Like cancer cachexia, EPA also impacts sepsis induced muscle wasting by down-regulating the muscle protein catabolism [34]. Additionally, EPA treatments in C2C12 cells induce skeletal muscle differentiation and prevent apoptosis and necrosis by reverting TNF␣ inhibitory effects. Studies show that TNF␣ inhibits the muscle differentiation either by blocking myogenesis in differentiating myoblasts and inducing apoptosis of myoblast/myotubes or by blocking peroxisome proliferator-activated receptor (PPAR␥; a major transcriptional regulator of lipid metabolism) activity. It is also evident that altered expression of PPAR␥ inhibits not only myotubes formation but also the expression of muscle-specific myogenic proteins (myogenin and MyoD). These findings illustrate the fact that EPA can promote muscle cells differentiation under pro-inflammatory cytokines mediated catabolic conditions [24,35]. Similar to EPA, fish oil (abundant in ␻3 PUFAs such as EPA and docosahexaenoic acid) is also very effective in regulating muscle pathophysiology. Studies have shown that dietary supplementation of fish oil prevents the LPS-induced inhibition of Akt signaling by decreasing forkhead box O1 (FoxO1) and FoxO4 abundance along with decreasing mRNA expression of muscle-specific E3 ubiquitin ligases i.e. muscle-specific F-box protein (MAFbx; atrogin1) and MuRF1, markers of the Ub–proteasome system in gastrocnemius and latissimus dorsi muscles of the pigs. This treatment reduced the TNF␣ and cyclooxygenase2 (Cox2) mRNA abundance in myofibers via regulation of muscle toll-like receptor (TLR) and nucleotide-binding oligomerization domain protein (NOD) signaling pathways, leading to improved skeletal muscle mass [25]. Studies also illustrate that fish oil or EPA inhibits the muscle degeneration and inflammation and ameliorates muscle physiological function as evaluated by grip test in dystrophindeficient (mdx) mice model [36]. Despite the above mentioned anti-cachectic effects of EPA such as gain in lean body mass, improvement in grip strength, reductions in pro-inflammatory cytokines (TNF␣, IL-6) in various cachectic conditions, few studies also reported the ineffectiveness of EPA in treating these conditions. Clinical results from randomized trials have suggested that EPA administration may not be effective in treating cancer cachexia. Likewise in another clinical trial, impact of EPA supplement was compared with megestrol acetate (standard cachexia treatment drug) in cancer cachexia where it was found that megestrol acetate is more effective than EPA in increasing body weight [22,37,38]. Overall these studies show that EPA regulates cachexia by reducing the expression level of large number of pro-inflammatory molecules such as TNF␣, IL-1, IL-6, PIF, Cox2, 15HETE, IKK, NF␬B, FoxO along with increasing the level of PPAR␥ which resulted in correcting the metabolic abnormalities as well as modulate the immune function (Fig. 2). However contradictory claims of other studies regarding ineffectiveness of EPA in cancer cachexia may limit its use. Further elaborate studies are needed to confirm its anti-cachectic role [39]. 2.1.2. ˇ-Hydroxy-ˇ-methylbutyrate (HMB) HMB a leucine metabolite is formed by trans-amination of leucine to ␣-ketoisocaproate in muscle followed by its oxidation in the cytosol of the liver. HMB is used as a therapeutic supplement to treat various muscle disorders [40–43]. HMB

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the loss of muscle mass [40]. The administration of HMB in combination with arginine and glutamine amino-acids to stage IV cancer patients, increased their body mass when compared to placebo [44]. Furthermore, HMB exerts protective effects against dexamethasone-induced atrophy by down-regulating the activated Akt/FoxO and MuRF1 levels which controls autophagy and ubiquitin dependent proteolytic systems [42,45]. HMB is also involved in the regulation of satellite cell proliferation probably through reduction of nuclear apoptosis [46]. Overall, HMB treatments regulate skeletal muscle wasting by stimulating protein anabolic and inhibiting protein catabolic pathways (Fig. 3).

Fig. 2. Schematic representation of EPA therapeutic action in tumor/cancer/sepsis cachexia.

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stimulates protein anabolism and inhibits protein catabolism under PIF-induced cachectic condition [41]. This suggests that HMB facilitates hyper-phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) resulting in the formation of active translation initiation complex (eIF4G:eIF4E). Besides this, HMB also up-regulates the phosphorylation of mammalian target of rapamycin (mTOR)/p70S6K pathway which is required for the formation of translation apparatus and elongation factors. Additionally, HMB reverses the PIF-induced auto-phosphorylation of double strand RNA-dependent protein kinase (PKR), leading to inhibition of phosphorylation of ␣-subunit of eIF2 resulting in accelerated translation process. In other words, HMB stimulates protein synthesis in muscle by activating multiple pathways leading to increased translation thereby compensating the loss of protein. In an experimental animal model of cancer-induced cachexia, HMB treatment not only down-regulated the expression of key regulatory components of 19S and 20S proteasome–proteolytic pathway but also stimulated protein synthesis which further regulates

2.1.3. Resveratrol Resveratrol (3,5,4 -trihydroxystilbene) is a natural polyphenol present mainly in peanuts, pines, skin of grapes, especially in red wine and exists both as cis- and trans-isomers. But the trans-isomer is the biologically active form [47–49]. Resveratrol is known to possess diverse therapeutic activities including anti-inflammatory, anti-atherosclerotic, anti-tumoral, cardioprotective, anti-diabetic and anti-oxidative effects [48,50–52]. A large number of studies performed in vitro and in vivo have confirmed that resveratrol treatment can prevent protein degradation induced by PIF, Angiotensin I and II, phorbal ester, 12-O-tetradecanoylphorbol-13acetetate (TPA), dexamethasone. In addition, resveratrol has shown its protective effect on muscle wasting under diverse catabolic conditions including cachexia and disuse [48,49,53]. Besides this, resveratrol treatment shows its anti-cachectic role by inhibiting NF␬B activity and MuRF1 expression in MAC16 tumor and C26 adenocarcinoma bearing mice [54,55]. Studies have shown that resveratrol regulates TNF␣ induced atrophy by up-regulating the phosphorylation of Akt, p70S6K, mTOR and 4E-BP1 and protects the dexamethasone-induced atrophy by inhibiting the increase in atrogin1 and MuRF1 expression via activation of SIRT1 (sirtuin, a histone deacetylase) and PGC-1␣ [48,49]. In streptozotocin induced diabetic rat model, resveratrol administration enhanced the insulin sensitivity, AMP-activated protein kinase (AMPK) and SIRT1 activities, and mitochondrial genesis and down-regulated the mRNA expression of pro-inflammatory cytokines (IL-1␤ and IL-6) and NF␬B expression [52,55]. Furthermore, resveratrol treatment for COPD decreases the levels of TNF␣ and increases the expression of SIRT1 which ultimately activates AMPK and regulates the

Fig. 3. Schematic representation of HMB therapeutic action in PIF/cancer/dexamethasone-induced atrophy.

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Fig. 5. Schematic representation of ghrelin/its mimetic therapeutic action in cancer, COPD, CKD, unloading induced muscle wasting.

Fig. 4. Schematic representation of reserveratrol COPD/diabetes/TNF␣/dexamethasone-induced atrophy.

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muscle wasting [56]. Pharmacokinetic and toxicological studies have revealed that higher doses of resveratrol (100 mg/kg/day) in humans and up to 700 mg/kg in rats do not show any adverse effects [51,57]. But there are conflicting data to show that resveratrol treatment is unable to reverse or block the loss of muscle mass and hence lacks anti-cachectic property as studied in rats bearing the Yoshida AH130 ascites hepatoma and in mice bearing the Lewis lung carcinoma [50]. Overall, various studies have indicated that resveratrol treatments control the muscle wasting and increase the muscle insulin sensitivity by down-regulating the level of pro-inflammatory cytokines and up-regulating the level of Akt, AMPK and SIRT1 in COPD/diabetes/TNF␣/dexamethasone-induced atrophy (Fig. 4). However, as Visioli rightfully cautions, these results from cell and animal studies may not always translate into similar results in human studies [58]. 2.1.4. Ghrelin and its receptor agonist Ghrelin (Growth Hormone Release-Inducing), a growth hormone (GH)-releasing polypeptide, is made up of 28 amino acids and mainly secreted from entero-endocrine cells of the stomach. This is found in both acylated and non-acylated forms. It binds to GH secretagogue receptor (formerly known as GHSR-1␣) and stimulates appetite via activation of neuropeptide Y (NY) in the hypothalamus and helps in regulation of body weight [59–61]. In skeletal muscles, it checks muscle wasting by down-regulating the TNF␣ mRNA expression without showing any significant effects on insulin-like growth factor-1 (IGF-1) mRNA in gastrocnemius muscle in a burninduced injury model. Ghrelin precursor peptide (des-acyl ghrelin, DAG) also has regulatory effect on TNF and IFN-induced skeletal muscle atrophy. This study shows that DAG attenuates the cytokine induced reduction in phosphorylation of Akt, FoxO1 and glycogen synthase kinase-3 beta (GSK3␤) in C2C12 myotubes. Besides

this, DAG also inhibits the activation of NF␬B and down-regulates atrogin1/MuRF1 mRNA expression [62,63]. In the lung adenocarcinoma induced cachexia, ghrelin treatment suppressed the inflammation by preventing the induction of TNF␣, IL-1␤, IL-6 and C-reactive protein (CRP). In addition, it also ameliorated skeletal muscle wasting by reducing the expressions of phosphorylated-p38 mitogen-activated protein kinase (p-p38MAPK), activated-NF␬B, FoxO1, MuRF1, and atrogin in the lysates of skeletal muscle of tumor-bearing mice [64]. Similar to its effect in cancer cachexia, ghrelin has shown positive results in regulating loss of skeletal muscle mass in chronic kidney disease (CKD) by enhancing mitochondrial oxidative capacity and Akt phosphorylation. These changes not only enhance insulin sensitivity but also favor skeletal muscle anabolism [60]. A clinical study which involved three week ghrelin treatment of cachectic patients with COPD and chronic heart failure (CHF), an increase in lean body mass and muscle strength pointed toward its anti-cachectic effect [59,65]. In another model of muscle wasting (unloadinginduced muscle atrophy), ghrelin administration acutely increased plasma GH and amplified phosphorylation of signal transducer and activator of transcription (STAT5), which increases IGF-1 mRNA expression in the plantaris muscle. This study illustrates that ghrelin alleviates muscle atrophy by stimulating GH-STAT5-IGF-1 axis in the atrophied muscle [66]. Although ghrelin plays a critical role in stimulating the appetite, increasing body mass and preventing muscle catabolism, its clinical effectiveness is limited due to its half life (30 min) and route of administration (intravenous) [67,68]. Additionally, a ghrelin receptor agonist, anamorelin HCl, has also demonstrated its positive effect in cancer anorexia–cachectic patients by increasing the level of GH, IGF-1, and insulin-like growth factor-binding protein 3 (IGFBP-3) which leads to increased appetite and body mass. Furthermore, it has better half life (7–12 h) compared to ghrelin (0.5 h) [69–71]. Though results of this drug are quite promising for cachexia treatment, further controlled studies with large sample size are still required to understand its efficacy and safety. From various reports it can be concluded that ghrelin has positive effect in controlling skeletal muscle wasting under diverse clinical settings such as cancer, COPD, CKD by up-regulating anabolic molecules (NY, GH, IGF-1, IGFBP-3, STAT5) and downregulating proteolytic systems (activated-NF␬B, FoxO1, MuRF1, and atrogin levels) (Fig. 5). In addition, by reducing the expression of inflammatory molecules including CRP, TNF␣, IL-1␤, and IL-6, this peptide shows systemic anti-inflammatory effect. Due to these promising features this drug is under Phase III clinical study.

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Fig. 6. Schematic representation of Cox2 inhibitors therapeutic action in cancer and arthritis induced atrophy.

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2.2. Enzyme inhibitors The mechanism of action of three different enzyme inhibitors will be discussed in this section. They are Cox2 inhibitors, histone decetylase inhibitors and phosphodiesterase (PDE) inhibitors. 2.2.1. Cox2 inhibitors Cyclooxygenase exists in multiple isoforms i.e. Cox1, Cox2 and Cox3. Of all these isoforms, Cox2 has pro-inflammatory actions and is induced by cytokines and mitogens not only in immune cells but also in other tissues including skeletal muscles. Cox2, a bifunctional enzyme, has both cyclooxygenase and peroxidase activities. The cyclooxygenase activity is responsible for the synthesis of prostaglandins (PGE2) from arachidonic acid while peroxidase activity can generate proximate carcinogens. These prostaglandins perform various actions via specific G-proteincoupled receptors and nuclear peroxisome proliferator-activated receptors (PPARs). Cox2 and PGE2 both are the downstream effectors of cytokine activity and mediate cachexia [72–75]. Preclinical and clinical trials strongly support the potential role for Cox2 inhibitors in the treatment of cancer [76]. So far a number of Cox2 inhibitors have been reported which inhibit PGE2 activity in diverse tumor bearing mice models and showed attenuating impact on the cachectic condition. Out of these inhibitors only two (celecoxib and meloxicam) have been widely used to study Cox2 mediated muscle loss [73,74,77]. 2.2.1.1. Celecoxib. Lai et al. performed a placebo-controlled study with celecoxib on 11 cachectic patients with either head and neck or gastrointestinal cancer. Interestingly, celecoxib treated patients showed a significant increase in body mass index and their quality of life improved as compared to placebo [78]. This reflects its effectiveness in treating cancer cachexia. To understand the efficacy and safety of celecoxib, Mantovani et al. performed a Phase II non-randomized study on cancer cachectic patients. The treatment group showed a significant increase in lean body mass and a decrease in TNF␣ along with improvement of grip strength and quality of life [76]. Not only in cancer cachexia, celecoxib showed its anti-cachectic role in diverse pathophysiological conditions. Rheumatoid arthritis cachectic rabbits when treated with celecoxib

showed reduction in the weight loss as well as in the level of inflammatory molecules (such as IL-6 and NF␬B) [79]. 2.2.1.2. Meloxicam. Meloxicam is another Cox2 inhibitor that inhibits the growth of murine adeno-carcinoma tumors (MAC 13, MAC16). Studies have shown that meloxicam treatment inhibits the LPS induced expression of Cox2, atrogin1 and MuRF1 and regulates the loss in muscle mass of rats by attenuating protein catabolism [75,77]. Similar to cancer, chronic arthritis also induces muscle wasting by mediating the Cox2 pathway. Studies show that Cox2 pathway not only inhibits the GH-IGF1 axis but also increases the TNF␣ and IGFBP-5 mRNA expression that contributes to the activation of ubiquitin–proteasome system and ultimately carry out degradation of muscle protein. However, administration of meloxicam ameliorated muscle loss by preventing arthritisinduced up-regulation of atrogin1 and MuRF1 in arthritic rats [80]. Fig. 6 illustrates the mechanism of action of Cox2 inhibitors in regulation of muscle wasting in cancer and arthritis patients 2.2.2. Histone decetylase inhibitors 2.2.2.1. Trichostatin A (TSA). TSA is a well known inhibitor of class I and II histone deacetylase. Just like phosphorylation/dephosphorylation, acetylation/deacetylation of cellular proteins is also involved in the regulation of muscle mass which is maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs) activities. Under atrophic condition, this process gets perturbed and causes de-gradation of muscle specific proteins by activation of proteolytic machineries [81,82]. In the denervation-induced muscle wasting, HDAC4 level is up-regulated which further increases the expression level of Ub–proteasome markers i.e. atrogin1 and MuRF1 by downregulating Dach2 level (a transcription factor and a repressor of the myogenin promoter) and accelerate the level of myogenin, a muscle-specific transcription factor essential for muscle development. Myogenin, in turn, creates a positive feedback loop and regulates HDAC4 expression [83,84]. Published data shows that under denervation condition (neuromuscular disorders), TSA modulates the level of atrogenes and control the muscle mass by reducing the HDAC4 activity and myogenin level, and increasing

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the expression level of Dach2 [85]. TSA treatment improves body weight, myofiber number and myofiber cross-sectional area [86]. Forkhead box O (FoxO), one of the transcription factors, necessary for muscle atrophy in various pathological conditions including muscle disuse and cancer, is directly regulated by acetylation and deacetylation process. A recent report shows that lysine acetylation of FoxO prevents its nuclear localization and makes it inactive while deacetylation process activates FoxO in disuse of skeletal muscles. Data illustrates that TSA inactivates FoxO by inhibiting the HDAC activity, which results in attenuation of skeletal muscle atrophy and contractile dysfunction [82]. Furthermore, TSA treatments to C2C12 myotubes under nutrient deprived atrophy, results in repression of FoxO target genes including Lc3 (a marker of autophagy), atrogin1 and MuRF1 [82]. Similarly, TSA treatment in the dexamethasone induced atrophic mice regulates muscle mass wasting by inhibiting atrogin1 and MuRF1 levels in C2C12 myoblast cells [85]. TSA treatment leads to increased muscle size and function in normal and dystrophic mice by inducing the expression of follistatin, an antagonist of myostatin (a negative regulator of skeletal muscle development). But TSA treatment to tumor-bearing mice increased the expression level of follistatin without preserving or increasing skeletal muscle mass. These studies show that alteration of myostatin/follistatin axis is not sufficient to protect muscle mass specifically in cancer-induced cachexia [87–89]. Such findings point to the fact that the outcome of TSA treatment is not same under diverse clinical settings. In studies on mdx mice model, Colussi et al. (2008, 2009), reported the role of nitric oxide (NO) as an epigenetic regulator in duchenne muscular dystrophy (DMD) and explained that NO countered the progression of muscular dystrophy by blocking the HDAC. Moreover, like TSA impact on dystrophic mice, NO also enhance the follistatin level and increase the myofiber length in mdx mice. In other words, the data thus depict that both (NO and HDAC inhibitor) can block the common target in DMD i.e. HDAC and up-regulate the expression of follistatin [90,91]. Overall published data illustrate that TSA regulates the muscle mass and contractile function by inhibiting HDAC mediated FoxO activation in different muscle wasting conditions (Fig. 7). Due to contradictory findings, further studies are needed to confirm the use of HDAC blocker to regulate atrophy [81,82,85]. 2.2.3. PDE inhibitors Cyclic adenosine 3 ,5 -monophosphate (cAMP), acts as an intracellular second messenger in response to diverse extracellular signals including hormones, neurotransmitters, growth factors and regulates a wide range of biological processes such as cell proliferation, differentiation, growth through its two receptor proteins i.e. PKA (cAMP-dependent protein kinase A) and Epac (exchange protein directly activated by cAMP). Phosphodiesterase (PDE) blocks the cAMP-dependent signaling by cleaving the diester ring of cAMP and decreases its level. Therefore use of PDE inhibitors is quite promising in regulation of diverse pathophysiological conditions including skeletal muscle atrophy. 2.2.3.1. Torbafylline (HWA 448). Torbafylline is a xanthine derivative which acts as a PDE inhibitor [92]. During burn injury, increase in the level of PDE4 plays prominent role in skeletal muscle proteolysis through activation of Ub–proteasome dependent proteolytic pathway. Various studies have highlighted that in skeletal muscles inhibition of PDE by torbafylline stimulates cAMP production and activates Epac which further catalyzes the activation of G-proteins i.e. Rap (Ras family of small GTPases), by facilitating the replacement of guanosine diphosphate (GDP) with guanosine triphosphate (GTP). The activated Epac-Rap GTPase pathway increases the level of phosphorylated-Akt and stimulates the protein anabolic

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Fig. 7. Schematic representation of TCS therapeutic action in denervation, muscle disuse, cancer, nutrient deprived induced atrophy.

pathways by activating the PI3K/Akt axis. This axis shows its positive effects on protein synthesis and inhibitory effects on protein degradation by elevating the level of phospho-GSK3␤ and phosphomTOR and decreasing the level of phospho-FoxO1 [13,93,94]. In addition, torbafylline treatment down-regulates mRNA expression of E3 ligases, cathepsin L, and calpain and regulates the proteolytic pathways in burn-induced injury. Besides this, torbafylline regulates muscle proteolysis by down-regulating the level of proinflammatory cytokines (IL-6 and TNF␣) probably by stimulating both (Epac and PKA) cAMP dependent receptor proteins [13,95,96]. In addition to injury induced atrophy, torbafylline attenuates inflammatory cytokine levels in a large number of muscle wasting models such as diabetes, cancer and sepsis [92,97,98]. These findings illustrate the anti-inflammatory properties of this compound. Furthermore, a torbafylline anti-atrophic effect has also been proved in denervation, casting or cancer induced cachexia models [92,97,99]. Overall it can be said that inhibition of PDE activity with torbafylline leads to stimulation of cAMP/Epac-Rap/PI3K/Akt pathway mediated anti-proteolytic effects in skeletal muscle atrophy (Fig. 8). 2.2.3.2. Pentoxifylline (PTX). Like torbafylline, PTX is another xanthine derivative that non-selectively inhibits PDE [92,99]. PTX is also known as suppressor of TNF␣ production [100,101] and this property makes it helpful in prevention of skeletal muscle wasting in cancer, sepsis, trauma, and AIDS models [92]. Published data show that PTX administration under diverse pathological conditions (diabetes, tumor, sepsis) in animal models stimulates cAMP formation and reduces the total rate of protein breakdown by down-regulating Ca2+ -dependent (calpain), Ca2+ -independent (cathepsin L) and proteasome (subunits of 20S and 26S) proteolytic system activities (Fig. 8) [98,101,102]. PTX seems to be effective in regulating the muscle wasting in diverse atrophic models while under septic condition torbafylline treatments attenuate proteasome activity with greater potency as compared to PTX [92]. Similar to these non-selective PDE inhibitors, selective inhibitors of PDE i.e.

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Fig. 8. Schematic representation of PDE inhibitors therapeutic action in tumor/diabetes/sepsis/burn induced atrophy.

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rolipram and cilomilast (Ariflo) have also been reported to reduce muscle atrophy in denervation and casting animal models [103].

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Skeletal muscles are rich in ␤2-adrenoceptors (␤2-AR) which are G-protein coupled receptors. On activation, this coupled complex activates PKA and cAMP response element binding protein (CREB) through stimulation of adenylate cyclase [104]. PKA phosphorylates CREB leading to its activation and binding to the DNA and inducing the expression of the myogenic transcription factors (Myf5, MyoD and Pax3) which regulates the myogenesis program [105]. In addition, CREB also promotes satellite cell proliferation and skeletal muscle regeneration after muscle injury [106]. In other words, ␤2-AR is involved in the regulation of skeletal muscle proliferation and differentiation programs and these properties make this receptor signaling pathway a novel therapeutic target for controlling the skeletal muscle wasting [107,108]. Some ␤adrenoceptor agonists include formoterol, clenbuterol and others which are under investigation regarding their potential to regulate skeletal muscle atrophy. 2.3.1. Formoterol Formoterol is a ␤2-AR agonist with anti-cachectic property. This compound has shown its therapeutic potential by stimulating skeletal muscle growth/hypertrophy and body weight not only by down-regulating the muscle specific proteolytic systems including Ub–proteasome and caspase-3 dependent apoptosis but also by inducing the protein anabolic response (i.e. Akt-dependent pathway). In addition to skeletal muscle, this compound has shown its powerful protective action on cardiac muscle as well [109,110]. In COPD patients, skeletal muscle dysfunction is usually responsible for limitations on physical exercise. Formoterol treatment enhances skeletal muscle oxidative process by increasing the PGC1␣ and mtDNA content in their skeletal muscles. As a result, the exercise capacity of COPD patients is gradually improved [111,112].

In the tumor-bearing rats, formoterol administration significantly increased the level of follistatin and decreased the levels of the myostatin and its receptor (activin IIB, ActIIB) thereby regulating the loss of muscle mass [108,113,114]. Various studies have demonstrated that myostatin suppresses the anabolic pathways (IGF-1/PI3K/Akt axis) and activates the catabolic pathways (p38MAPK/ERK1/2, Wnt and FoxO1 signaling and Ub–proteasome system) while follistatin binds to myostatin and antagonizes its function [115–119]. Furthermore, formoterol administration in bupivacaine-treated rats ameliorates muscle wasting by increasing Pax7 and decreasing myogenin mRNA content which further stimulates satellite cell proliferation and favors muscle regeneration. In addition, formoterol can induce mitochondrial biogenesis to prevent dexamethasone induced atrophy [120,121]. Beneficial effect of formoterol was also observed under both cancer cachexia (Yoshida AH-130 ascites tumor bearing rat) and sarcopenic conditions. These studies suggest that ␤2-AR agonist treatment leads to reduced muscle wasting by regulating the loss of muscle mass [110,122].

2.3.2. Clenbuterol Clenbuterol is another ␤2-AR agonist which stimulates the cAMP level and suppresses the fasting-induced expression of atrogin1 and MuRF1 by inducing Akt/FoxO3 phosphorylation [104]. Clenbuterol administration under denervation induced atrophy, regulates the muscle wasting process through activation of protein anabolism and inhibition of cathepsin L and Ub ligases dependent proteolytic system. Studies have shown that these effects of clenbuterol are possibly mediated through cAMP/PKA signaling pathway without involving Akt [14]. Similar regulatory role of clenbuterol has also been demonstrated in other atrophic experimental animal models such as hind-limb suspension, immobilization, and spinal cord injury. As shown in Fig. 9(a) and (b), overall these drugs regulate muscle wasting through diverse mechanisms that include down-regulation of apoptosis, rate of protein catabolism,

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Fig. 9. (a) Schematic representation of ␤-agonist therapeutic action in tumor/dexamethasone/sarcopenic induced atrophy. (b) Schematic representation of ␤-agonist therapeutic action in fasting/denervation induced atrophy.

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Cytokines (such as TNF␣, TWEAK, IL-1, IL-6) are the major culprits in almost any kind of pathophysiological condition that leads to chronic inflammation and ultimately results in loss of skeletal muscle. Therefore, use of antibodies against such cytokines could be beneficial in regulating loss of skeletal muscle. There are many studies that have highlighted the beneficial effect of some of these antibodies such as anti-TNF␣, anti-IL-1 and anti-IL-6 on halting the muscle loss and restoring their function. Some of these antibodies are under Phase I/II/III trials (Table 1). More detailed information about other anti-cytokines except anti-TNF␣ that are beneficial in treating cancer cachexia can be found in the review article by Ma et al. [123]. 2.4.1. Anti-TNF˛ Studies have shown that administration of an anti-murine TNF IgG in rats bearing the Yoshida AH-130 ascites hepatoma down-regulates not only the level of circulatory TNF␣ and muscle ubiquitin gene expression, but also controls the protein degradation in skeletal muscles [124]. Likewise, injection of soluble-TNF receptor (sTNFR1, specific inhibitors of TNF␣), in monocratiline (MCT) treated Sprague–Dawley rats prevent the interaction of TNF␣ with its receptors and attenuates the MAFbx and ubiquitin transcription. This study illustrates that anti-TNF␣ treatment reduces the skeletal muscle wasting in cardiac cachexia and preserves the body mass [102]. Interestingly, Granado et al. reported the opposite effect of sTNFR1 on arthritic rat. They observed that administration of polyethylene glycol linked-sTNFRI to arthritic rats does not alter the gastrocnemius muscle mass and MuRF1/MAFbx gene expression [125]. 2.4.2. Thalidomide Thalidomide (a glutamic acid derivative) was first introduced in 1951 as a sedative compound and later as an anti-emetic. It was widely used by pregnant women for treating morning sickness and became notorious for birth defects. As a result thalidomide was pulled out of market. Later this compound gained intense interest because of its anti-TNF␣ activity. As a result Food and Drug

Administration (FDA) has approved this drug in 1998 for treatment of erythema nodosum leprosum (Leprosy reaction variant) [126,127]. Presently, there is renewed interest in thalidomide for its extensive array of actions such as anti-inflammatory, anti-angiogenic, immuno-modulator along with anti-emetic and sedative activities. Additionally, this compound has shown its anticachectic property in cancer patients by down-regulating the TNF␣ mRNA expression. Like other drugs mentioned above, thalidomide also prevents the nuclear translocation of NF␬B by inhibiting the activity of I␬B kinase and preserves the skeletal muscle mass in cachexia [28]. Besides this, thalidomide reduces the serum levels of IL-6 and CRP in the cancer-cachexia patients [128–130]. Liu et al. [131] reported that thalidomide can preserve the fast-twitch type skeletal muscle fibers in tumor induced cachexia by decreasing the expression of TNF␣ and transforming growth factor beta1 (TGF␤1) in the soleus muscle of cholangiocarcinoma rats. TGF␤1 is a negative regulator of muscle mass which inhibits Akt-dependent pathway (protein anabolic pathway) via Smad2/Smad3 and enhances the proteolysis of muscle specific proteins [132]. Kaplan and co-workers observed the anti-cachectic effect of thalidomide in AIDS associated muscle wasting patients. Such patients when treated with thalidomide (100 mg/day and 200 mg/day) showed a significant improvement in weight compared to the placebo treated group [133]. Similarly, another research group worked with pancreatic cancer cachexia patients and observed significant weight gain in thalidomide treated patients [19]. Tumor-associated macrophages express Cox2 that acts as a source for prostaglandins (PGE) production. These PGE impairs immune surveillance by inhibiting several T-cells and natural killer cell functions. Report shows that thalidomide and its derivatives inhibit the lipopolysaccharide (LPS) induced Cox2 and PGE2 synthesis in murine macrophages [134,135] and control the systemic inflammation. In addition to anti-inflammation and anti-cachectic activity, thalidomide treatment (Phase II trial) has also shown its impact on appetite in 64% of the patients who are in advanced stage of cancer [130]. Overall thalidomide inhibits the activity/expression of various pro-inflammatory cytokines and transcription factors such as TNF␣, TGF␤1, IL-6, CRP, Cox2 and NF␬B and shows its tremendous therapeutic potential by preventing the loss of muscle mass in tumor/cancer/AIDS induced cachexia (Fig. 10). Thalidomide also been reported to cause several side effects including peripheral neuropathy, dizziness, constipation, and rashes [132].

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Table 1 Molecules effected by drugs used under diverse clinical settings. S. no

Name of drug

Model used for study

1. Natural compounds A.

Eicosapentanoic acid

Tumor/cancer/sepsis induced atrophy

B.

␤-Hydroxy-methyl butyrate (HMB)

PIF/cancer/ dexamethasone-induced atrophy

C.

Reserveratrol

COPD/diabetes/TNF␣/ dexamethasone-induced atrophy

D.

Ghrelin and des acyl ghrelin (appetite stimulant)

Cancer, COPD, CKD, unloading induced muscle wasting

Celecoxib (Cox2 inhibitor)

Cancer and arthritis induced cachexia Cancer and arthritis induced cachexia

2. Enzyme inhibitors A. Cox2 inhibitor I. II.

B. Histone deacetylase inhibitor I.

C. PDE inhibitor I.

II.

3. ␤-Adrenoceptor agonists A.

B.

4. Anti-cytokine agents A.

Meloxicam (Cox2 inhibitor)

Molecules affected Inhibits: IL-1, TNF␣, IL-6, NF␬B, 15LOX, caspase-8, FoxO Increases: p-Akt, PGC-1␣/PPAR␥ Inhibits: FoxO, MuRF1 Ub–proteasome (regulatory subunits of 19S and 20S) Increases: eIF4G:eIF4E (translation initiation complex), PKR, mTOR and p70S6K Inhibits: TNF␣, IL-1␤, IL-6, NF␬B, MuRF1 Increases: Akt, mTOR, p70S6K, 4E-BP1 AMPK and SIRT1, Inhibits: NF␬B, FoxO1, MuRF1, atrogin1, TNF␣, IL-1␤, and IL-6 Increases: growth hormone, IGF-1, IGFBP-3, neuropeptide Y

Phase II trial completed

Inhibits: Cox2, TNF␣, IL-6, NF␬B, PGE2 Inhibits: Cox2, TNF␣, IGFBP-5, atrogin-1, MuRF1 Increases: GH-IGF1 axis

Trichostatin A (HDAC inhibitor)

Denervation, muscle disuse, cancer, nutrient deprived induced atrophy

Inhibits: class I and II histone deacetylases, FoxO, atrogin-1/MAFbx, MuRF1 and Lc3, myogenin Increases: Dach2 (negative myogenin regulator),

Torbafylline (PDE inhibitor)

Tumor/diabetes/sepsis/burn induced muscle wasting

Pentoxifylline (PDE inhibitor)

Tumor/diabetes/sepsis/burn induced muscle wasting

Inhibits: PDE, IL-6, TNF␣, ubiquitin, E3-ligase, Cathepsin L and Calpain Increases: cAMP, Akt Inhibits: TNF␣, cathepsin L, Calpain, 20S and 26S proteasome

Formoterol

Tumor/dexamethasone/ sarcopenic induced atrophy

Clenbuterol

Denervation and fasting induced atrophy

Anti-TNF

Rats bearing the Yoshida AH-130 ascites hepatoma Non-small cell lung cancer (NSCLC)-related anemia and cachexia Cancer cachexia

B.

ALD518 (anti-IL6)

C.

E.

MABp1 (anti-IL-1␣) IP-1510 (IL-1 receptor antagonist) sTNFR1

F.

Thalidomide

D.

Trial phase

Cancer cachexia Monocratiline (MCT) treated Sprague-Dawley rats Tumor/cancer/AIDS induced cachexia

Inhibits: myostatin, caspase-3, Wnt, FoxO1, atrogin, MuRF1 Increases: follistatin, IGF1/PI3K/Akt, Pax7 Inhibits: FoxO3, atrogin, MuRF1, cathepsin L Increases: cAMP, phospho-Akt, PGC-1␣

TNF␣, ubiquitin and MAFbx Phase I and II completed

IL-6

Phase I complete, Phase III under trial Phase I and II complete

IL-1␣ IL-1 receptor antagonist TNF␣, MAFbx/MuRF1, ubiquitin

Phase II trial

Inhibits: TNF␣, IL-6, Cox2, PGE2, NF␬B, TGF␤1 Increases: Akt

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Table 1 (Continued) S. no

Name of drug

Model used for study

Trial phase

5. Other investigational drugs A. B.

Ostarine GLPG0492

Cancer cachexia Hindlimb immobilization, DMD Cancer cachexia Cancer cachexia

Phase II trial

Healthy adults individuals

Phase II under trial

Sporadic inclusion body myositis Cancer cachexia

Phase II, III under trial

C. D.

OHR/AVR118 APD209

E. F.

REGN1033 (anti-myostatin) BYM338

G.

ACVR2B

6. Miscellaneous agents A.

712

713 714 715 716 717 718 719 720 721 722 723 724 725

726 727 728

Megesterol acetate (MA)

Tumor/cancer/AIDS cachexia

2.5. Other investigational drugs 2.5.1. Enobosarm Enobosarm (also called ostarine, GTx-024) is a non-steroidal, orally bio-available and a selective androgen receptor modulator (SARM). It has shown a dose-dependent improvement in total lean body mass and physical function in healthy elderly men and postmenopausal women. Besides this, enobosarm is also useful in the prevention of muscle wasting associated with cancer cachexia. Data from Phase II clinical trial where cancer patients were administrated with ostartine showed improvement in muscle performance (measured by stair climb) and insulin resistance without any visible side effect and toxicity. Hence enobosarm possesses a strong efficacy and safety in cancer cachexia conditions to regulate muscle loss [136–138]. 2.5.2. GLPG0492 GLPG0492 (galapagos) is another non-steroidal SARM that has shown its efficacy on muscle by increasing muscle fiber size and

Fig. 10. Schematic representation tumor/cancer/AIDS cachexia.

of

thalidomide

therapeutic

action

in

Phase IIb trial Phase II pilot trial

Molecules affected

Inhibits TNF␣ and IL-6. ␤-Adrenoceptor agonist, act like megesterol and formoterol Myostatin (MSTN) Blocking the activin type II B receptor Inhibit signaling of MSTN/activin

Inhibits: IL-1, IL-6, and TNF␣, Ub–proteasome system, E2 ligase and atrogin-1 Increases: neuropeptide Y secretion

skeletal muscle function in the hindlimb of immobilized mice and in duchenne muscular dystrophy (DMD) patients respectively. This drug is in preclinical trial to treat DMD [139,140]. 2.5.3. OHR/AVR118 It is a broad-spectrum peptide-nucleic acid immune-modulator with anti-inflammatory activity that targets both cellular proinflammatory chemokine and cytokine synthesis (such as TNF␣ and IL-6). A Phase II trial of this drug on patients with advanced cancer and cachexia achieved stabilization of body weight, body fat and muscle mass with a significant increase in appetite without showing any adverse effect. This study shows that OHR/AVR118 drug diminishes the harmful effects of such cytokines/chemokines, whose activation has a direct effect on muscle metabolism. Besides cancer cachexia patients, this drug has also been used for treatment of AIDS cachexia patients, where it helped in alleviating multiple symptoms of the disease [141,142]. 2.5.4. APD209 APD209 is an oral, fixed-dose combination of megestrol (a progestin which is used off-label in cachexia) and formoterol (a selective ␤-adrenoceptor agonist) for use in treatment of cancer cachexia. A Phase IIa trial study with this drug on patients with cancer-related anorexia and cachexia syndrome (CACS) demonstrated improved muscle size and strength [143,144]. Hence it may be a potential new drug for treating cachexia in the future. 2.5.5. Anti-myostatin/activin Available evidences suggest that members of the TGF-␤ superfamily such as myostatin (MSTN) and activin A are powerful catabolic stimuli that inhibit muscle growth and promote muscle protein loss in various disease states [145,146]. Both these ligands bind initially with activin type II receptor (ActRIIB and ActRIIA) and then with activin type I receptor (activin-like kinase; ALK-4 or ALK5) to activate cytosolic SMAD2/3 proteins which leads to proteolysis and cause muscle fiber atrophy. It has been reported that inhibition of the myostatin ameliorates the dystrophic phenotype in the mdx mouse model, sarcopenia in an aging mouse model and muscle wasting in tumor-bearing mice [88,147–149]. Bimagrumab (BYM338) and REGN1033 are two human monocloncal antibodies against myostatin. The treatment with BYM338 enhances differentiation of primary human skeletal myoblasts and increases skeletal muscle mass in mice by blocking the activin type II B receptors (ActRIIB). However REGN1033 administration prevents loss of muscle mass in dexamethasone or immobilization

Please cite this article in press as: V. Dutt, et al., Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.05.010

729 730 731

732 733 734 735 736 737 738 739 740 741 742 743 744

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within 2 weeks. This soluble receptor is also very effective in preventing cardiac muscle atrophy in tumor-bearing mice [88,145]. During a Phase II clinical trial of ACE031 with DMD patients and healthy volunteers, some participants experienced gum bleeding, nosebleeds as well as dilation in skin blood vessels which led to discontinuation of the trials. Overall BYM338, REGN1033 and soluble ActRIIB/Fc are promising drugs that have the ability to regulate muscle wasting/cachexia by blocking MSTN/activin signaling under diverse pathological conditions including cancer and may further help in improving the rate of mortality and morbidity.

2.6. Miscellaneous agents

Fig. 11. Schematic representation of megesterol acetate therapeutic action in tumor/cancer/AIDS cachexia.

771 772 773 774 775 776 777 778 779 780 781 782 783

induced muscle wasting by directly antagonizing the myostatin [123]. Presently, BYM338 is under Phase II/III trial to treat sporadic inclusion body myositis patients (a rare life-threatening musclewasting condition) while REGN1033 is in Phase II to treat patients with sarcopenia [150,151]. Though various endogenous regulators including follistatin usually blocks MSTN signaling and maintains the muscle mass, some studies have suggested that even increase in the level of follistatin is ineffective in preserving muscle in cancer cachexia [87]. However, systemic administration of a soluble form of the activin type IIB receptor (ActRIIB/Fc; ACVR2B-ACE031) in mice bearing cancer cachexia can inhibit MSTN signaling and its related ligands like activin and significantly increases muscle growth (40–60%)

2.6.1. Megestrol acetate In 1993, FDA approved megestrol acetate (MA) for the treatment of cancer and AIDS induced cachexia. More than 15 clinical trials have demonstrated that at 160–1600 mg/day, this drug significantly improves appetite and the lean body mass. This drug is being used either alone or as a supplement along with meloxicam for cachectic cancer patients where it has shown positive effects in regulating the loss of body mass [23,152,153]. MA is used to improve appetite and weight gain in AIDS/cancer induced anorexia–cachexia syndrome [154–156]. Though the mechanism of stimulation of appetite/increased body mass is not clear, studies have shown the involvement of neuropeptide Y and suppression of pro-inflammatory cytokines such as IL-1, IL-6, and TNF␣ [23,157,158]. These studies have shown that in MA-treated rats, the food and water intake significantly increased when compared to untreated group. The levels of NY in the lateral hypothalamic area increased indicating that NY may be responsible for this orexigenic (appetite-stimulating) effect. Another study have shown that administration of MA in tumor (Yoshida AH-130 ascites hepatoma)-bearing rats results in reversal of muscle wasting process by decreasing the mRNA level of ubiquitin, E2 and atrogin1 which are the key biomarkers of Ub–proteasome proteolytic system [159]. These studies suggest that MA, either alone or as a supplement with meloxicam, can be used to stimulate appetite in cancer/AIDS induced cachectic patients. It causes down-regulation of inflammation mediated molecules such as IL-1, IL-6, TNF␣, ubiquitin, E2, atrogin1 and up-regulation of NY level. This leads to increased appetite, body mass, and decreased muscle protein degradation

Fig. 12. Drugs and their overall inhibitory effect on skeletal muscle specific proteolytic system.

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by suppressing the Ub–proteasome mediated proteolytic system (Fig. 11). MA treatment is also associated with some adverse effects. If the treatment is discontinued abruptly it can lead to thromboembolic phenomena, peripheral edema, hyperglycemia, hypertension, adrenal suppression and adrenal insufficiency [22].

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3. Conclusions

824 825 826 827 828

849

Up-regulation of skeletal muscle protein breakdown is hallmark of atrophy and as a result all potential drugs target the proteolytic systems to cure or prevent the skeletal muscle atrophy. As shown in Table 1 and Fig. 12, all the drugs have displayed positive effects in diverse atrophic models either by inhibiting particular molecules/cytokines/proteolytic systems involved in protein catabolic pathway or by improving the satellite cell function during muscle injury and aging. In spite of this, except MA, no other drug has yet been recommended by FDA to prevent or treat muscle atrophy. This underlines the fact that the reported drugs are not efficiently targeting every proteolytic system. It can be safely inferred that skeletal muscle atrophy being a multi-factorial syndrome, needs a multi-targeted approach to yield success. There are reports in literature regarding use of some non-pharmacological therapies (such as nutritional supplement and rehabilitation) to delay the onset of disease and ease its symptoms at least up to some extent and improve the quality of life [160]. Thus there is the need for combinational treatment and developing a novel approach to treat skeletal muscle wasting.

850

Conflict of interest

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All authors (VD, SG, RD, EI, AM) declare that they have no conflicts of interest involving this work.

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Acknowledgments

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G Model YPHRS 2837 1–16 14 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059

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G Model YPHRS 2837 1–16

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