Polyphenols and their potential role in preventing skeletal muscle atrophy

Journal Pre-proof Polyphenols and their potential role in preventing skeletal muscle atrophy

Sara Salucci, Elisabetta Falcieri PII:

S0271-5317(19)30570-6

DOI:

https://doi.org/10.1016/j.nutres.2019.11.004

Reference:

NTR 8069

To appear in:

Nutrition Research

Received date:

16 June 2019

Revised date:

18 October 2019

Accepted date:

18 November 2019

Please cite this article as: S. Salucci and E. Falcieri, Polyphenols and their potential role in preventing skeletal muscle atrophy, Nutrition Research(2019), https://doi.org/10.1016/ j.nutres.2019.11.004

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Journal Pre-proof Polyphenols and their potential role in preventing skeletal muscle atrophy Sara Salucci and Elisabetta Falcieri Department of Biomolecular Sciences, University of Urbino Carlo Bo Corresponding author: Sara Salucci, Department of Biomolecular Sciences, University of Urbino

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Carlo Bo, Italy. Email : [email protected]

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Journal Pre-proof Abbreviations mTOR, mammalian target of rapamycin; akt, serine/threonine kinase; UPS, ubiquitin proteasome system; MuRF1, Muscle RING-finger protein-1; NF-ĸB, Nuclear Factor kappa-light-chainenhancer of activated B cells; ROS, reactive oxygen species; AMP, adenosine monophosphate; IGF-1, insulin-like growth factor-1; MyoD, Myoblast Determination Protein 1; PGC-1α, Peroxisome proliferator-activated receptor coactivator 1-alpha; SMN2, survival of motor neuron 2;

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DMD, Duchenne muscular dystrophy; SIRT1, NAD-dependent deacetylase sirtuin-1; AMPK, 5'

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AMP-activated protein kinase; TNF-α, tumor necrosis factor-alpha.

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Journal Pre-proof ABSTRACT Skeletal muscle atrophy is the consequence of various conditions, such as disuse, denervation, fasting, aging, and disease. Even if the underlying molecular mechanisms are still not fully understood, an elevated oxidative stress correlated to mitochondrial dysfunction has been proposed as one of the major contributors to skeletal muscle atrophy. Researchers have described various forms of nutritional supplementation to prevent oxidative stress-induced muscle wasting. Among a

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variety of nutrients, attention has also focused on polyphenols, a wide range of plant-based

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compounds with antioxidant and inflammatory properties, many of which have beneficial effects on

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human health and might retard skeletal muscle loss and function impairment. The purpose of this review is to describe polyphenol actions in skeletal muscle atrophy prevention. Published articles

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from the last ten years were searched on PubMed and other databases. Polyphenols are important

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molecules that should be considered when discussing possible strategies against muscle atrophy. In particular, the collected studies describe, for each polyphenol subclass, the beneficial effect on

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muscle mass preservation in various skeletal muscle disorders. In these examples, the polyphenol

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compounds appear to mainly act by reversing mitochondrial dysfunction. Given that the current

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information on polyhenols is mostly restricted to basic studies, more comprehensive research and additional studies should be performed to clarify their mechanisms of action in improving skeletal muscle functions during atrophy.

Key words Skeletal muscle atrophy, skeletal muscle disorders, oxidative stress; polyphenols, antioxidants

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1. Introduction This review introduces the main pathways of skeletal muscle wasting. Literature in this area was searched from multiple databases, including PubMed, Scopus, and Web of Science, to identify molecular and cellular mechanisms involved in muscle atrophy. In particular, key words used for the search of the literature in the last twelve years were: muscle atrophy pathway, mitochondrial dysfunctions and muscle wasting, oxidative stress vs muscle atrophy, protein synthesis vs protein

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degradation, molecular mechanism in mass loss. This review focused attention on the role of

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polyphenols in muscle atrophy

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Skeletal muscle atrophy, characterized by mass loss and muscle function decline, is due to an

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increase in muscle protein degradation and reduced protein synthesis [1, 2]. Muscle mass reduction is frequently associated with a high inflammatory state [3] and occurs in several conditions, such as

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starvation, aging, immobilization, spinal cord injury, inflammatory myopathies, and various genetic

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muscle disorders such as muscular dystrophy [4-6]. One of the most widely recognized major

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players in controlling muscle mass is the mammalian target of rapamycin (mTOR), a serine/threonine kinase activated by various environmental and intracellular changes, including nutrient availability and energy status [7,8]. A decreased activation of the Akt-mTOR pathway contributes to protein synthesis reduction, which can occur under disuse conditions [9, 10] or after a low protein diet [11].

In general, the major degradation mechanisms in skeletal muscle include the lysosomal system, caspases, and ubiquitin proteasome pathways [12]. However, the ubiquitin proteasome system (UPS) is considered the most important proteolytic system in muscle wasting [12-15]. The main ubiquitin ligases identified in skeletal muscle are the atrogin‐1/MAFbx and muscle RING finger 1 (MuRF1), which are up-regulated during muscle loss or inflammation. The MuRF1 is a potent 4

Journal Pre-proof trigger of muscle wasting, which involves NF‐κB transcription factor activation, and proteasomal degradation. Figure 1 describes the principle pathways involved in protein synthesis and degradation. It appears clearly that an up-regulation of TNF or IL-1 induces the activation of some substrates, which lead to the ubiquitin ligase up-regulation, and thus, to proteosomal degradation. Moreover, stress signals pathways contribute to mitochondrial damage and ROS increase, which can lead to NF-ĸB or AMPK up-regulation and Foxo activation, contributing to muscle degradation

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(Figure 1).

Oxidative stress, characterized by increased reactive oxygen species (ROS) production and

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impairment of antioxidant defense systems, can be considered a major trigger of imbalance between

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protein synthesis and degradation leading to muscle atrophy [16-19], as found in the pathogenesis

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of chronic and degenerative disorders [20-25]. In skeletal muscle, high levels of ROS promote proteolytic process activation [26-31] as well as mitochondria dysfunction with impairment of

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mitochondria membrane functions and a reduction in mitochondria biogenesis [32, 33]. ROS is

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reported in various atrophic conditions [34, 35], myopathies [36, 37], and muscular dystrophies [38-

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40]. Therefore, ROS and redox disturbances may represent important signaling events in skeletal muscle atrophy [27, 41, 42, 43]. Nonetheless, whether oxidants are the major contributors to muscle atrophy remains controversial and counteracting them represents an important goal in muscle atrophy prevention.

The use of antioxidants to reduce oxidative stress associated damage has been shown to be effective against muscle atrophy [44, 45, 46]. Antioxidants could have a significant potential as complementary therapies counteracting the damaging effects of chronic inflammation or elevated oxidative stress. A number of molecules, such as melatonin [47, 48], Coenzyme Q10, creatine [49], vitamins D and E, and others, have been reported for clinical merit in muscle dysfunctionalities [50, 51]. Among antioxidants, polyphenols have demonstrated beneficial effects on low-grade 5

Journal Pre-proof inflammation and oxidative stress damage; however, little is known about their effect on skeletal muscle atrophy.

2. Approach To investigate polyphenols and their contributioin in the prevention or delay of muscle disorders correlated to muscle mass loss, we searched the relevant literature published from 2011 to 2019 in the PubMed database. The following key words were applied in the literature search: Polyphenols

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and muscle atrophy or polyphenols and skeletal muscle damage or natural antioxidants and muscle dysfunctionalities or polyphenols and muscle disorders. The search was performed on primary

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research investigations and review articles that afforded some potential actions of polyphenol

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involvement in preventing muscle loss in physiological and pathological conditions. In particular, to

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highlight the contribution of each polyphenol subclass, we selected the term nomenclature. Thus, we further searched in the PubMed database by adding the following terms: phenolic acid and

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muscle atrophy or flavonoids and muscle wasting or Resveratrol in muscle damage or stilbenes in

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muscle damage or lignans in skeletal muscle disorders.

In the present review, we discuss the contributions of the principal polyphenols belonging to each chemical subclass, which have shown significant effects in counteracting muscle loss in various conditions such as myopathies, distrophyes, aging, disuse, and others.

Polyphenols are the largest group of phytochemicals that contribute to protection of diseases related to oxidative stress response. In recent years, polyphenols have been extensively studied with regard to their roles in the prevention of neurodegenerative diseases and skeletal muscle atrophy. Dietary polyphenols constitute one of the most numerous and widely distributed groups of natural products in the plant kingdom. Fruits, vegetables, whole grains, and other types of plant-based foods and

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Journal Pre-proof beverages such as tea, chocolate, and wine are rich sources of these antioxidant compounds [52, 53].

Polyphenols are classified on the basis of the number of phenol rings in their molecule and of the structural elements that bind these rings to one another. Therefore, they are divided into four classes: phenolic acids, flavonoids, stilbenes, and lignans [54]. The chemical structure of each polyphenol group and their principal derivatives and main food sources are shown in Figures 2-7,

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which refer to each polyphenol subclass.

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2.1 Phenolic Acids

Phenolic acids are non-flavonoid polyphenolic compounds which can be further divided into two

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main types, benzoic acid (gallic acid) and cinnamic acid (caffeic acid, p-coumaric acid) derivatives

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(Figure 2). Few reports describe the beneficial effects of benzoic or cinnamic acid on skeletal

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muscle. However, Pierno et al. (2014), showed the synergic activity of gallic acid (Figure 2) with homovanillic as preventing skeletal muscle function decline due to aging-associated oxidative stress [55]. Another study revealed that sumaric extract antioxidant activity is due to its content of phenolic compounds. In particular, its protective effect could be from gallic acid but at low concentrations; however, it is cytotoxic at high concentrations since it provokes DNA damage and suppresses DNA repair genes [56]. Low intakes of sumaric fruit, containing a low concentration of gallic acid, could delay the progression of skeletal muscle atrophy, thus playing a major role in the modulation of the cellular aging process, as demonstrated in zebrafish embryos [57].

Hydroxycinnamic acid is known for its ability to modulate glucose uptake and lipid metabolism through the AMP activated protein kinase signalling pathway [58]. p-Coumaric acid (Figure 1) is 7

Journal Pre-proof part of this phenolic family and is reported to have antioxidant, anti-inflammatory, and anti-cancer activities [59, 60]. In skeletal muscle cells it seems to inhibit differentiation by decreasing the expression of Myogenin and MyoD [61]. Of particular merit is its derivative, i.e. curcumin (Figure 3), a natural tumeric polyphenol compound with beneficial effects on several diseases, including skeletal muscle disorders. In fact, curcumin delays skeletal muscle mitochondrial impairment in rats affected by chronic obstructive pulmonary disease. In this case curcumin up-regulated the PGC-1α pathway, which controls the expression of various genes involved in mitochondrial metabolism and

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biogenesis [62]. In addition, in mice, curcumin prevented an increase of myotube protein degradation and it is effective in the reduction of muscle mass loss, thanks to its capacity to inhibit

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protein ubiquitination, inflammation, and oxidative stress [63, 64]. Curcumin also attenuated the

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inflammatory action of palmitate in C2C12 cells. In this case, it acts by reducing ROS production

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and by down-regulating nuclear factor kappa B (NF-kB), which plays a central role in muscle development, maintenance, and regeneration. In fact, high NF-kB expression induces the

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proteolytic cascade activation [65]. Recently, Chaudhary et al. (2019), also demonstrated that

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curcumin administration prevents the decline in myofibrillar protein degradation under hypobaric

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hypoxia. This is a condition characterized by up-regulation of the ubiquitin proteasome pathway, which causes loss of skeletal muscle mass by involving high levels of oxidative stress. In this case, curcumin modulates ROS levels, which are the principal regulators of the proteolytic pathways [66].

Another component of the hydroxycinnamic acid family is caffeic acid (Figure 2), which is found in fruits, wine, and coffee. It has been shown to have anti-oxidant, anti-inflammatory, antimetastatic, and anti-tumour effects [67], and it also appears to be a potential candidate for improving the symptomatology of autosomal recessive spinal muscular atrophy. This latter genetic disease is characterized by selective loss of α motor neurons in the anterior horn of the spinal cord, leading to neurogenic muscle atrophy. Caffeic acid and curcumin are able to increase SMN2 expression, an 8

Journal Pre-proof important gene that modulates the severity of the disease, and the treatment with these polyphenols could ameliorate motor abilities and reduce neurodegeneration, preserving muscle functions [68]. A preliminary in vitro study on murine myoblasts demonstrated the beneficial effect of hazelnut oils, which contain several anitoxidant compunds, among these, caffeic acid. Hazelnut oils, in fact, stimulate myoblast differentiation and cell muscle hypertrophy, and they could afford an application

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in counteracting catabolism and atrophy [69].

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2.1.1 Extra virgin oil phenols

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Many studies have demonstrated the beneficial effects of dietary sources of extra virgin olive oil on

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human health. The oil contains phenolic compounds that appear to reduce oxidative damage, improve cardiovascular health, and delay aging [70, 71, 72]. Olive oils are composed mainly of

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triglycerides, fatty acids, tocotrienols, essential fatty acids (i.e. linoleic acid, as polyunsaturated

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omega-6), and phenolic compounds, including tyrosol and hydroxytyrosol (Figure 4), and their

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metabolic derivatives that are thought to be responsible for the antioxidant effects [73]. Hydroxytyrosol and hydroxytyrosol acetate show several benefits for muscle function as well [55, 71]. The ability of hydroxytyrosol to prevent strenuous exercise-induced muscle dysfunction, to reduce muscle lipid accumulation in mice fed with a high-fat diet, and to delay cell death induced by oxidative stress has been demonstrated [74, 75]. This compound shows a synergic effect with other nutrients in improving disuse-induced muscle atrophy [76]. Moreover, Wang et al. (2014) [77] described the protective effect of hydroxytyrosol-acetate on oxidative stress-induced mitochondrial dysfunction and muscle degeneration in C2C12 cells. More recently, Villani et al. (2018) [78] demonstrated the actions of extra virgin oil polyphenols in ameliorating the sarcopenic phenotype of older, adult rats. In addtion, tyrosol is an active scavenger in various cell models; however, nothing is known about its action on muscle. Therefore, for the first time, Salucci et al. (2018) [79] 9

Journal Pre-proof investigated the potential beneficial effect of tyrosol in counteracting glucocorticoid-induced muscle atrophy in an in vitro skeletal cell model.

2.2 Flavonoids

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For their positive effects on human health, flavonoids are the most studied molecules in the family

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of polyphenols. The flavonoids include many different subclasses: flavones, flavonols, flavanones,

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flavanonols, isoflavones, and anthocyanidins (Figure 5). Among them, flavonols are present in food as both glycosides and aglycone forms, and it has been estimated that the human daily intake is

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within the range of 20–50 mg/d in Western populations. Quercetin and myricetin are the most

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abundant flavonols in the Western diet [54]. Quercetin (Figure 5), mainly present as quercetin glycosides, is widely distributed in plant food. It is found in apples, berries, onions, grapes, tea, and

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tomatoes as well as in some medicinal plants, such as Hypericum perforatum and Gingko

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skeletal muscle [81].

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biloba [80]. Quercetin aglycone and its metabolites can be found in several tissues, including

These natural plant-based compounds appear to target the mitochondria, improves their function, and likely affords some protection against muscle atrophy in several wasting conditions [82, 83, 84]. In particuar, dietary quercetin supplementation counteracts oxidative damage in atrophied skeletal muscle by reducing lipid peroxidation [82]. In skeletal muscle wasting diseases, such as Duchenne muscular dystrophy (DMD), the up-regulation of PGC-1α appears to maintain muscle function and protect muscle from inflammation, metabolic dysfunction, and free radical injury. Several studies identify quercetin as a promising therapeutic supplement able to up-regulate PGC1α [85, 86], and thus, to partially protect dystrophic skeletal muscle from cell damage. More recently, some researchers demonstrated that quercetin exerts positive effects on TNFα10

Journal Pre-proof induced skeletal muscle atrophy in obese conditions [87]. Chan et al. [88] showed that quercetin may suppress muscle wasting associated with the expression of atrophy gene-1 and MURF-1 to increase the myosin heavy chain level in gastrocnemius muscles. Human and animal studies indicate a correlation between quercetin supplementation, endurance capacity, and mitochondrial biogenesis improvement. For example, Davis et al. [89] published interesting results showing that a 7 day quercetin treatment (12.5 or 25 mg/kg b.w.) increased the expression of genes associated with mitochondrial biogenesis (such as PGC-1 α and SIRT1), mitochondrial DNA content, and

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cytochrome c concentration, both at muscle and brain levels in mice.

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Dihydromyricetin, the main flavonoid component of A. grossedentata ,displays a broad range of

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biological and pharmacological activities such as antioxidant, anti-inflammatory, anti-tumor,

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neuroprotective, and hepatoprotective effects [90, 91]. This compound could reverse mitochondrial dysfunction in skeletal muscle under acute hypoxic conditions [92]. Moreover, it restores

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PGC-1α signaling pathway [93].

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mitochondrial function and delays dexamethasone-induced muscle atrophy by up-regulating the

Another source of flavonoid is licorice, which was found to down-regulate the expression of MuRF1 and atrogin-1, two markers of muscle atrophy [94]. Moreover, Apigenin, a flavone abundantly found in fruits and vegetables, exhibits antiproliferative, anti-inflammatory, and anti-metastatic activities and shows the capacity to attenuate mitochondrial dysfunction by preventing obesity‐induced skeletal muscle atrophy [95].

Ampelopsin, a natural flavonoid, has multiple biological functions including anti-inflammatory, anti-oxidative, and hepatoprotective functions. It exerts its action of decreasing ubiquitin and Atrogin-1/MAFbx and in up-regulating AMPK and SIRT1 signaling pathways by attenuating skeletal muscle atrophy associated with aging [96]. 11

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Panduratin A has anti-obesity, anti-bacterial, anti-cancer, anti-inflammatory, and anti-oxidative activities and might be a useful agent for the treatment of muscle atrophy. In fact, in TNF-alphatreated L6 rat skeletal muscle cells, panduratin A restored the myotube diameter and stimulated the MyoD and myogenin mRNA expression reduced by TNF-α [97].

Oligonol, a low molecular weight polyphenol derived from lychee, exhibits anti-diabetic and anti-

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obesity properties, and it appears to be a potentially useful supplement for attenuating muscle loss in diabetes, as demonstrated by Liu et al. (2017). Oligonol was reported to suppress Atrogin-1 and

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MuRF1 activation [98]. It is known that during periods of skeletal muscle disuse, , a sedentary

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lifestyle or bed rest for example, is associated with aging and can lead to muscle atrophy. The

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flavan 3-ol fraction, derived from cocoa, delays disuse muscle atrophy induced by hindlimb suspension in mice [99]. Moreoever, isoflavin-beta (Iso-β), a mixture of isoflavones with

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antioxidant properties, prevents thyrotoxicosis-induced loss of muscle mass [100].

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Delphinidin, one of the major anthocyanidins, shows several protective properties against cancer, inflammation, and muscle atrophy. In particular, Delphinidin delays disuse muscle atrophy by suppressing MuRF1 expression [101].

Within the flavonol subclasses, there is a family of secondary metabolites known as catechins. They are found in a number of foods and plants, such as green tea and cacao. Catechins consist mainly of epigallocatechin gallate, gallocatechin gallate, and epicatechin gallate, which are bioavailable and afford cardioprotective, antiatherogenic, and anticarcinogenic effects [102, 103]. Green tea or green tea extracts contain high levels of polyphenolic catechins [104], showing antioxidant and antiinflammatory properties. These effects are in part due to their abilty to down-regulate NF-ĸB pathway, which is up-regulated in muscles of DMD patients and in mdx mice (same dystrophin 12

Journal Pre-proof mutation as human patients) [105]. Moreover, some studies demonstrate that green tea supplementation prevented muscle damage and preserved neuromuscolar function induced by a cumulative fatigue condition [106, 107]. Green tea extracts, with beneficial effects on obesity, hyperglycemia, and insulin resistance, are also able to prevent high-fat diet-induced muscle weight loss in a murine model of senescence [108]. Takahashi et al. (2017) [109] demonstrated that green tea reduced apoptotic signaling and improved muscle recovery in response to reloading after hindlimb suspension. In particular, green tea suppressed Beclin1, ATG7, and LC3-II/I protein

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expression, which were up-regulated in hindlimb muscles, where these autophagic proteins act inimproving the clearance of damaged mitochondria via mitophagy. After reloading, green tea

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administration is able to suppress autophagy signaling, by reducing the autophagic protein content

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(such as Beclin 1, ATG7 and LC3II) and, as a consequence, it exerts a fundamental role in restoring

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muscles mass and function [109]. Moreover, sarcopenia, a multifactorial disorder characterized by the loss of muscle mass and functionality, seemed to be improved from cathechin supplementation.

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For example, in sarcopenic rats treated with green tea, a preserved muscle mass was shown when

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compared to untreated rats. This action of green tea appears to be due to, at least in part, the

2.3 Stilbenes

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attenuation of protein degradation via the ubiquitin-proteasome pathway [110].

Stilbenes (Figure 6) are natural compounds found in certain types of plants that provide some potential health benefits [111, 112]. Resveratrol (Figure 6) is one of the naturally occurring polyphenols that belongs to the stilbenes group, is well known for its great health benefits, and is frequently found in berries, grapes, wine, and some other fruits and vegetables [113]. It plays an important role in the transcription of two important antioxidant enzymes, the superoxide dismutase and catalase [114, 115]. As a consequence, stilbenes enhance the expression of various antioxidant defensive enzymes and maintains the cellular redox balance acting on glutathione levels [116]. In 13

Journal Pre-proof particular, resveratrol showed an interesting benefit in skeletal muscle as well. Momken et al. (2011) [117] demonstrated a significant reduction of muscle disuse atrophy in rats supplemented with resveratrol before unloading or muscle immobilization. In addition, some studies examined the ability of resveratrol to correct metabolic deficiencies responsible for myopathies and that contributed to DMD pathogenesis. In this sense, treatment with resveratrol inhibited muscle atrophy in mdx mice, in a mouse model of cancer cachexia, and in an aging-correlated disuse condition

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[118, 119, 120].

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Resveratrol seems to act by involving mitochondrial metabolic targets, by inducing the activation of

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various molecules such as PGC-1 alpha, SIRT1, and/or AMP-kinase, apoptotic, and antioxidant enzymes [121-124]. Therefore, resveratrol has the potential to prevent dexamethasone-induced

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mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving

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mitochondrial activity [84]. In addition, resveratrol treatment or its combination with a moderate

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exercise preservation of gastrocnemius muscle mass loss in aged rats is probably due to the activation of the AMPK/SIRT1 pathway [125]. Recently, Asami et al, (2018) [126] demonstrated

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the attenuation of denervation-induced muscle atrophy in resveratrol-treated mice. In this condition, resveratrol seems to act by reducing the atrogin-1-dependent system and by improving the autophagic defects through AMPK activation.

2.4 Lignans

Few studies report the effects of lignans in skeletal muscle wasting; however, one example of potential actions is for magnolol, a lignan extracted from Magnolia officinalis (Figure 7), that has some capacity to inhibit inflammation, angiogenesis, and cancer growth [127, 128]. For the first 14

Journal Pre-proof time, Chen et al. (2015) demonstrated that mice treated with magnalol showed an improvement of

atrophic phenotype [129]. Magnolol seems to act by up-regulating IGF-1 and by inhibiting myostatin formation and inflammation. Recently, other lignans have been tested for in vitro studies on murine C2C12 skeletal muscle cells. For example, Schisandrin A and C are able to reduce ROS increase, favoring mitochondria biogenesis and maintaining their functionality [130, 131].

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3. Discussion The available literature suggests that bioactive polyphenols, known for their effects on degenerative

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and chronic diseases, can also provide protection against skeletal muscle damage because of their

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potential actions of antioxidants and anti-inflammatory properties. This review examined the

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current literature on the potential roles of polyphenols in limiting or delaying muscle wasting. These data were mainly collected from cell culture experiments or animal studies and demonstrate

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positive outcomes regarding some muscle disorders, where polyphenol administration showed

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benefits in ameliorating the symptomatology of muscle loss diseases. In particular, this review

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provides evidence for how some polyphenols such as green tea, resveratrol, and others [85, 86, 105, 118, 119] show beneficial effects by reducing inflammation and reactive oxygen species in dystrophic animal models. In contrast, the therapy for treating muscular dystrophy is based on corticosteroid treatment, which is often characterized by serious adverse side effects. Therefore, polyphenols, naturally found in food products, appear to produce similar effects to those observed after cortocosteroid supplementation, and likely represent a potentially valid alternative in the treatment of DMD patients [51]. Furthermore, this review provides evidence for the use of polyphenols as potential therapeutic agents in various physiological or pathological states like aging, sarcopenia, immobilization, denervation, malnutrition, and cachexia [55, 78, 98, 99, 108, 110, 126].

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Journal Pre-proof The literature supports the premise that oxidative stress is involved in skeletal muscle diseases by increasing the levels of lipid and protein oxidation, thus leading to mitochondrial dysfunction, which can be considered a common feature in atrophy-correlated skeletal muscle disorders. Therefore, mitochondria play a crucial role in skeletal muscle dysfunctions, and the protection of this organelle from injury seems crucial to the prevention of skeletal muscle damage. As a consequence, the beneficial effects of polyphenols are partly due to their ability to improve mitochondrial oxidative metabolism by up-regulating mitochondrial biogenesis through the

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involvement of various substrates. Figure 8 is a schematic illustration that describes the main pathways which could be activated in the presence or absence of polyphenol treatment in muscle

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disorders. The evidence in this review highlights the involvement of SIRT1, AMPK, and PGC-1α

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signalling in the presence of dietary polyphenols in animals affected by atrophic disorders.

Findings from polyphenol administration suggest possible opportunities to control high ROS levels,

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restore mitochondria functionality and activation of the AKT-mTOR pathway in physiological

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situations of muscle loss and disease. Therefore, further studies should investigate these

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transcription factors, by focusing attention on SIRT1, AMPK, and PGC-1α, which could become therapeutic targets where polyphenols act to promote or modulate direct inhibition of pathways of protein breakdown related to atrophic conditions.

4. Conclusions This review summarized the evidence on polyphenols which have been shown to have merit in preventing skeletal muscle disorders and atrophy. However, there are some unknown aspects which should be further investigated. More research is needed to elucidate polyphenol mechanisms of action in preventing muscle atrophy. Moreover, limited evidence is available to compare the efficacy of different polyphenols, both in vivo and in vitro. As a consequence, further 16

Journal Pre-proof studies are essential to define the dosage and duration of polyphenol supplementation in animal studies and controlled, clinical trials. Indeed, the polyphenol synergic effect should also be investigated with regard to antioxidant potential and the clinical benefit in different skeletal muscle atrophic conditions. Additional research is a practical approach given that polyphenols are a natural component of a healthy diet and there are many food products that contain these

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compounds.

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Acknowledgment

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This work has been possible thanks to the DISB 2017 Enhancement Project of Urbino University.

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The authors declare no conflict of interest.

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Journal Pre-proof Figure legends Figure 1 Schematic illustration of the main pathways involved in protein synthesis and degradation and the inflammatory factors and genes. The arrows show substrate activation and impact of mitochondial damage.

Figure 2

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Chemical structures of benzoic (gallic acid is the main phenol) and cinnamic (p-coumaric and caffeic acid are the main compounds) acids. Green tea and fruits are the source of benzoic acid, while cinnamic acid can be found in fruits, vegetables, coffee, and cider.

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Figure 3

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Chemical structure of curcumin, and its main source is tumeric. Figure 4

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Figure 5

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Oil derived polyphenol chemical structures, and their sources are olives and olive oil.

Chemical structure of the principal flavonoid classes. Flavones can be found in parsley, celery, hot pepper, and thyme. The flavonol sources includes onion, curly kale, leek, cherry, tomato, broccoli, apple, green and black tea, and blueberry. Flavanones sources are lemon, orange, and grapefruit juice. The isoflavones sources are legumes, soy milk, tofu, and miso. Anthocyanidins sources are strawberry, plum, black grapes, blueberry, black currant, cherries, and rhubard.

Figure 6 Stilbene and resveratrol chemical structures. These compounds are present in red wine, black skin fruits, peanuts, and blueberries.

Figure 7 Magnolol (from lignans) chemical structure, and its food sources include seeds and nuts. 34

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Figure 8

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Schematic illustration of the possible main pathways of polyphenol actions in the treatment of skeletal muscle disorders. The evidence suggests that polyphenols appear to preserve muscle mass and support protein synthesis. The illustration shows that if muscle disorders are not treated with polyphenols, protein degradation is a primary consequence. The two micrographs, obtained by an environmental scanning electron microscopic examination [79], represent the concept for how polyphenols may work. In particular, panel A shows myotubes pre-treated with a polyphenol before atrophic induction, and this micrograph is representative of muscle mass preservation. Panel B shows the myotubes exposed to a drug treatment able to mimic muscle wasting, indicating muscle size reduction, suggesting an up-regulation of protein degradation (red arrows: upregulation; blue arrows: down-regulation). .

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Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8