Nutritional research may be useful in treating tendon injuries

Accepted Manuscript Nutritional Research May Be Useful in Treating Tendon Injuries Luke Curtis, MD, MS PII:

S0899-9007(15)00536-5

DOI:

10.1016/j.nut.2015.12.039

Reference:

NUT 9679

To appear in:

Nutrition

Received Date: 4 September 2015 Revised Date:

13 November 2015

Accepted Date: 25 December 2015

Please cite this article as: Curtis L, Nutritional Research May Be Useful in Treating Tendon Injuries, Nutrition (2016), doi: 10.1016/j.nut.2015.12.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

1

NUTRITIONAL RESEARCH MAY BE USEFUL IN TREATING TENDON INJURIES

3

Luke Curtis, MD, MS, Curtis Research, 12570 Portland Avenue S #223,

4

Burnsville, MN 55337, USA [email protected]

SC

5

RI PT

2

Abstract

7

Tendon injures cause a huge amount of disability, pain, and medical costs.

8

However, relatively little is known about tendon biology and healing. Many

9

tendon related surgical procedures are not very successful and leave the

10

patient with essentially a chronic injury. New therapeutic approaches for

11

tendon injury are needed. Preliminary evidence suggests that various

12

nutrients such as protein, amino acids (leucine, arginine, glutamine), vitamins

13

C+D, manganese, copper, zinc, and phytochemicals may be useful to improve

14

tendon growth and healing.

15

Much more research on nutrition and tendon health is needed. Since many

16

nutrients are required for tendon health, nutritional interventions involving

17

multiple nutrients may be more effective than single nutrient strategies. In the

18

future, ideal treatment regimens for tendon injuries may include a multifaceted

19

“bundle” of nutrition, drugs, biological products, extracellular matrix therapies,

20

exercise/ physical therapy, and possibly surgery.

AC C

EP

TE D

M AN U

6

1

ACCEPTED MANUSCRIPT

21

Keywords: tendon, Achilles tendon, rotator cuff, tenocytes, vitamin C, amino

23

acids, manganese, copper, zinc, phytochemicals.

RI PT

22

24

Introduction

26

Tendon injuries cause a great deal of pain, disability, and medical & economic

27

costs [1, 2]. The exact prevalence of tendon injuries is unknown, but it is

28

estimated that worldwide over 30 million patients have tendon-related surgical

29

procedures annually at a medical cost of over €140 billion per year (about US$

30

196 Billion) [3]. Surgical repairs for tendon injuries require a long and painful

31

recuperation and are often not very successful, leaving the patient with

32

essentially a permanent injury [3-7]. Clearly, better treatments for tendon

33

injuries are needed.

34

Tendon healing is generally a very slow and incomplete process [1, 6-8]. Use of

35

biological and biomaterial approaches, such as use of platelet rich plasma,

36

extracellular matrix (ECM)/ scaffold treatments, regulation of growth factors

37

and cytokines, and stem cell based approaches, potentially offer promise in

38

speeding up and improving repair of torn or otherwise damaged tendons [1, 3,

39

5, 8, 9]. There is a dearth of both basic and applied tendon research, and our

40

basic understanding of tendon biology lags far behind that of muscle or bone

41

[1, 2, 6, 7] .

AC C

EP

TE D

M AN U

SC

25

2

ACCEPTED MANUSCRIPT

The purpose of this short review is twofold: 1) To describe existing research on

43

nutrition and tendon health/ healing and: 2) To stimulate interest in clinicians

44

and researchers to consider nutritional approaches as a partial strategy in

45

treating tendon problems.

RI PT

42

46

Methods

48

About 110 research and review articles were collected for information about for

49

studies relating tendons with nutrition and related topics. Animal and cell

50

culture studies were included as in vivo studies of nutrition and tendons in

51

humans is currently sparse. Various Medical Database were searched for

52

articles include PubMed, Google and Google Scholar, FDA.Gov, and clinical

53

trials.gov. No time restriction was placed on the search. Searched terms

54

included a variety of tendon related terms including tendon, tendonitis, tendon

55

tears, Achilles tendon, rotator cuff, patellar tendon, tenocytes, collagen, leucine

56

rich proteins, and proteoglycans. Many nutritional related terms were also

57

used including calories, omega 3 fats, protein, amino acids (such as leucine,

58

glutamine, arginine and taurine), fruits, vegetables, phytochemicals, vitamins

59

(including all of the various vitamins), minerals (Ca, Mg, Zn, Cu, Mn, Fe, Mo,

60

Si) and coenzyme Q10. A total of 33 articles were selected for citing in this

61

review if they were deemed to have relevance in exploring relationships between

62

tendons and nutrition.

AC C

EP

TE D

M AN U

SC

47

3

ACCEPTED MANUSCRIPT

63

Nutrition and Tendon Growth and Healing

65

Nutrition may play a major role in tendon healing, although research has been

66

sparse to date. The majority of work to date has involved animals or cultured

67

human cells, although there are a few clinical human studies. Some animal

68

and human studies report significantly better tendon growth or collagen

69

synthesis following various nutritional interventions. Supplementation with

70

19.5 grams per day of whey protein was found to significantly increase patellar

71

and quadricep tendon cross sectional area in a group of 22 young men

72

concurrently in an exercise program [10]. Vitamin C is necessary for the

73

enzymatic synthesis of both collagen proteins and several proteoglycans found

74

in tendons [11]. Vitamin C is also a transcriptional promoter of collagen

75

synthesis [12]. A rat study reported that high dose oral vitamin C

76

supplementation significantly accelerated healing of ruptured Achilles tendons

77

[12]. Another rat study reported that a vitamin D deficient diet significantly

78

slowed healing and buildup of biomechanical strength of the rotator cuff [13].

79

High dose oral glucosamine/ chondroitin sulphate was found to significantly

80

accelerate tendon to bone healing in rabbits [14]. Taurine injected at the

81

tendon repair site was found to significantly improve load strength in rats with

82

repaired Achilles tendons [15]. Deficiencies of biotin, folate, or manganese

83

were found to significantly increase tenosynovitis in reovirus infected chickens

84

[16].

AC C

EP

TE D

M AN U

SC

RI PT

64

4

ACCEPTED MANUSCRIPT

Since collagen forms the major extracellular protein in tendons, muscle, and

86

ligaments [1, 11, 17] dietary interventions to increase collagen synthesis

87

and/or protein synthesis in general may be helpful in rebuilding tendons.

88

Such dietary interventions might include providing sufficient overall calories/

89

protein and supplementation with such nutrients as trace minerals and/or

90

amino acids. Numerous animal and human studies have reported that diets

91

deficient in protein and/or calories lead to significantly less collagen

92

production [11]. Many trace minerals such as zinc, copper, and manganese

93

play a key role in collagen metabolism, and nutritional deficiencies in these

94

minerals have been linked to poorer collagen synthesis [18, 19]. Amino acid

95

supplementation with glutamine, arginine, and branched chained amino acids

96

(leucine, isoleucine, and valine) was found to significantly increase skin

97

collagen synthesis in UV-irradiated mice [20]. Various studies have reported

98

that dietary consumption of leucine or its metabolite ß-hydroxy-ß-

99

methylbutyrate (HMB) simulate protein synthesis via signaling pathways

TE D

M AN U

SC

RI PT

85

involving mTOR(mammalian target of rapamycin) in a dose–response manner

101

[21]. Other studies have reported that oral supplementation of mixtures of

102

HMB, glutamine, and arginine can significantly increase muscle and/or lean

103

mass in a wide variety of patients including the elderly [22], cachectic HIV

104

patients [23], and muscle-wasted cancer patients [24].

105

Since many nutrients are involved with tendon and collagen metabolism,

106

nutritional interventions employing multiple nutrients may yield better results

AC C

EP

100

5

.

ACCEPTED MANUSCRIPT

as compared to studies employing only one nutrient. A human study of 90

108

patients with rotator cuff surgery reported that the use of a multifaceted

109

Tenosan® supplement containing 1 gram of arginine l-alpha- ketoglutarate, 1.1

110

grams methylsulfonylmethane, 600 mg hydrolyzed collagen, 120 mg. vitamin

111

C, and 100 mg bromelain daily was associated with significantly better repair

112

integrity at final follow-up [25]. A human study of patients with insertional

113

Achilles tendinopathy treated 32 patients with the Tenosan supplement

114

(mentioned above) and 32 patients with placebo. All patients also underwent 3

115

courses of extracorporeal shockwave therapy. After 6 months pain was

116

significantly reduced and patient satisfaction was significantly increased in the

117

Tenosan treated patients as compared to the placebo treated patients [26].

118

In vitro studies also suggest that various nutrients like phytochemicals from

119

plants or Ω-3 fats may be useful for tendon repair and health. Cyanidin is a

120

colored pigment found in many fruits and vegetables including red cabbage,

121

cherries, bilberries, serviceberries, red and black grapes, blueberries, and

122

blackberries. Cyanidin (100 µg/ml) was found to inhibit autophagic cell death

123

in human rotator cuff tenoblasts [27]. Curcumin (a diarylheptanoid found in

124

turmeric) was found to significantly reduce inflammation in human tenocytes

125

[28]. A study of Achilles tendons from orofloxicin treated rats reported that

126

degenerative changes were significantly more common in rats fed a magnesium

127

deficient diet as compared to a magnesium sufficient diet [29]. A supplement

128

containing vitamin C, collagen type 1, manganese, and mucopolysaccharides

AC C

EP

TE D

M AN U

SC

RI PT

107

6

ACCEPTED MANUSCRIPT

showed significant anti-inflammatory and anti-catabolic effects of human

130

tenocytes in vitro [30] . The Ω-3 fatty acid EPA (eicospentaenoic acid) was

131

found to enhance collagen formation in cultured human medial collateral

132

ligament fibroblasts [31] .

133

Proteoglycans are proteins found in the tendons’ extracellular matrix (ECM)

134

which play a critical role in the function and structure of tendons. The two

135

main classes of tendon proteoglycans include: 1) small leucine rich

136

proteoglycans (SLRPs) including decorin, fibromodulin, lumican, and biglycan;

SC

M AN U

137

138

RI PT

129

these proteins bind to collagen fibrils and 2) large molecular proteoglycans such as aggrecan and versican which are associated with tendon loading and

140

mobilization [32, 33]. Perhaps nutritional interventions with leucine and/or

141

other nutrients may improve synthesis and function of tendon proteoglycans.

142

Understanding of the relationships between nutrition and tendon proteoglycans

143

is lacking and major research in this area is clearly needed.

144

SUMMARY

145

Table 1 below summarizes various human, animal and cell culture studies

146

which suggest that various nutrients may be helpful to tendon health, growth

147

or repair.

AC C

EP

TE D

139

148

7

ACCEPTED MANUSCRIPT

Table 1- Human, Animal, and Cell Culture Studies which Suggest the Following Nutrients May be Helpful in Tendon Health, Growth, and Repair and/or Collagen Synthesis. Numbers listed refer to references.

Whey Protein

[10]

Animal StudiesMammals or Birds

[12]

Vitamin D

[13]

Glucosamine / Chondroitin Sulfate

[14]

Taurine

M AN U

Vitamin C

Cell Culture Studies or Animal Organs

RI PT

Human Studies

SC

Nutrient

[15]

Biotin, Folate, Manganese

[16]

Calories

[11]

Protein

[11]

[11]

[20]

TE D

Glutamine, Arginine, Leucine, Isoleucine, Valine

[11]

[25, 26]

AC C

EP

Tenosan®. 1 gram of arginine l-alphaketoglutarate, 1.1 grams methylsulfonylmethane, 600 mg hydrolyzed collagen, 120 mg. vitamin C, and 100 mg bromelain daily. Cyanadin (Phytochemical found in many fruits/ vegetables)

[27]

Curcumin

[28]

Magnesium

[29]

Vitamin C, Collagen Type

[30] 8

ACCEPTED MANUSCRIPT

Table 1- Human, Animal, and Cell Culture Studies which Suggest the Following Nutrients May be Helpful in Tendon Health, Growth, and Repair and/or Collagen Synthesis. Numbers listed refer to references. Human Studies

Animal StudiesMammals or Birds

Cell Culture Studies or Animal Organs

RI PT

Nutrient

1, Manganese, & Mucopolysaccharides

[31]

SC

EPA or Eicospentaenoic Acid (Ω-3 Fatty Acid)

M AN U

149

CONCLUSION

151

Much more research and clinical attention is needed to develop better

152

treatment strategies for torn or damaged tendons. Most of the research on

153

tendons and nutrition have dealt with animal or cell culture studies which may

154

or may not be representative of the effects of nutrition and tendon health in

155

humans. Additional research on human nutrition and tendon health/repair is

156

needed. Most nutritional interventions interventions are fairly inexpensive and

157

have a low risk of side effects. A “bundle” of multiple interventions may be

158

needed for optimal tendon growth and healing. In the future, ideal treatment

159

for tendon injuries may include a multifaceted program of good nutrition/

160

supplements, drugs, biological products/ stem cells, extracellular matrix/

161

scaffold therapies, exercise/ physical therapy, and possibly surgery.

162

REFERENCES

AC C

EP

TE D

150

9

ACCEPTED MANUSCRIPT

163

8. 9.

10.

11. 12.

13.

14. 15. 16. 17.

18. 19. 20.

21.

RI PT

6. 7.

SC

4. 5.

M AN U

3.

TE D

2.

Docheva D, Muller SA, Majewski M, Evans CH: Biologics for tendon repair. Adv Drug Deliv Rev 2015, 84:222-239. Nourissat G, Berenbaum F, Duprez D: Tendon injury: from biology to tendon repair. Nat Rev Rheumatol 2015, 11(4):223-233. Lomas AJ, Ryan CN, Sorushanova A, Shologu N, Sideri AI, Tsioli V, Fthenakis GC, Tzora A, Skoufos I, Quinlan LR et al: The past, present and future in scaffold-based tendon treatments. Adv Drug Deliv Rev 2015, 84:257-277. E P: Tending tender tendons. Science 2002, 295:1011. Randelli P, Randelli F, Ragone V, Menon A, D'Ambrosi R, Cucchi D, Cabitza P, Banfi G: Regenerative medicine in rotator cuff injuries. Biomed Res Int 2014, 2014:129515. Gaut L, Duprez D: Tendon development and diseases. Wiley Interdiscip Rev Dev Biol 2015. Dyment NA, Galloway JL: Regenerative biology of tendon: mechanisms for renewal and repair. Curr Mol Biol Rep 2015, 1(3):124-131. Voleti PB, Buckley MR, Soslowsky LJ: Tendon healing: repair and regeneration. Annu Rev Biomed Eng 2012, 14:47-71. Shea KP, McCarthy MB, Ledgard F, Arciero C, Chowaniec D, Mazzocca AD: Human tendon cell response to 7 commercially available extracellular matrix materials: an in vitro study. Arthroscopy 2010, 26(9):1181-1188. Farup J, Rahbek SK, Vendelbo MH, Matzon A, Hindhede J, Bejder A, Ringgard S, Vissing K: Whey protein hydrolysate augments tendon and muscle hypertrophy independent of resistance exercise contraction mode. Scand J Med Sci Sports 2014, 24(5):788-798. Berg RA, Kerr JS: Nutritional aspects of collagen metabolism. Annu Rev Nutr 1992, 12:369-390. Omeroglu S, Peker T, Turkozkan N, Omeroglu H: High-dose vitamin C supplementation accelerates the Achilles tendon healing in healthy rats. Arch Orthop Trauma Surg 2009, 129(2):281-286. Angeline ME, Ma R, Pascual-Garrido C, Voigt C, Deng XH, Warren RF, Rodeo SA: Effect of dietinduced vitamin D deficiency on rotator cuff healing in a rat model. Am J Sports Med 2014, 42(1):27-34. Taskesen A, Ataoglu B, Ozer M, Demirkale I, Turanli S: Glucosamine-chondroitin sulphate accelerates tendon-to-bone healing in rabbits. Eklem Hastalik Cerrahisi 2015, 26(2):77-83. Akdemir O, Lineaweaver WC, Cavusoglu T, Binboga E, Uyanikgil Y, Zhang F, Pekedis M, Yagci T: Effect of taurine on rat Achilles tendon healing. Connect Tissue Res 2015, 56(4):300-306. Cook ME, Springer WT: Effect of reovirus infection and dietary levels of selected vitamins on immunocompetence of chickens. Avian Dis 1983, 27(2):367-377. Babraj JA, Cuthbertson DJ, Smith K, Langberg H, Miller B, Krogsgaard MR, Kjaer M, Rennie MJ: Collagen synthesis in human musculoskeletal tissues and skin. Am J Physiol Endocrinol Metab 2005, 289(5):E864-869. Keen CL Z-CS: Manganese. 1996:334-343. Burch RE, Hahn HK, Sullivan JF: Newer aspects of the roles of zinc, manganese, and copper in human nutrition. Clin Chem 1975, 21(4):501-520. Murakami H, Shimbo K, Inoue Y, Takino Y, Kobayashi H: Importance of amino acid composition to improve skin collagen protein synthesis rates in UV-irradiated mice. Amino Acids 2012, 42(6):2481-2489. Rennie MJ: Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass. Biochem Soc Trans 2007, 35(Pt 5):1302-1305. 10

EP

1.

AC C

164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208

ACCEPTED MANUSCRIPT

244

26.

27. 28.

29.

30. 31.

32. 33.

RI PT

SC

25.

M AN U

24.

TE D

23.

Baier S, Johannsen D, Abumrad N, Rathmacher JA, Nissen S, Flakoll P: Year-long changes in protein metabolism in elderly men and women supplemented with a nutrition cocktail of beta-hydroxy-beta-methylbutyrate (HMB), L-arginine, and L-lysine. JPEN J Parenter Enteral Nutr 2009, 33(1):71-82. Clark RH, Feleke G, Din M, Yasmin T, Singh G, Khan FA, Rathmacher JA: Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy betamethylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. JPEN J Parenter Enteral Nutr 2000, 24(3):133-139. May PE, Barber A, D'Olimpio JT, Hourihane A, Abumrad NN: Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg 2002, 183(4):471-479. Gumina S, Passaretti D, Gurzi MD, Candela V: Arginine L-alpha-ketoglutarate, methylsulfonylmethane, hydrolyzed type I collagen and bromelain in rotator cuff tear repair: a prospective randomized study. Curr Med Res Opin 2012, 28(11):1767-1774. Notarnicola A, Pesce V, Vicenti G, Tafuri S, Forcignano M, Moretti B: SWAAT study: extracorporeal shock wave therapy and arginine supplementation and other nutraceuticals for insertional Achilles tendinopathy. Adv Ther 2012, 29(9):799-814. Kim RJ, Hah YS, Sung CM, Kang JR, Park HB: Do antioxidants inhibit oxidative-stress-induced autophagy of tenofibroblasts? J Orthop Res 2014, 32(7):937-943. Buhrmann C, Mobasheri A, Busch F, Aldinger C, Stahlmann R, Montaseri A, Shakibaei M: Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem 2011, 286(32):28556-28566. Shakibaei M PK, Schwabe R, Vormann J, Stahlman R: Ultrastructure of Achilles tendomn of rats treated with ofloxacin and fed a normnal or magnesium-deficient diet. Antimicrob Agents Chemother 2000, 44:261-266. Shakibaei M, Buhrmann C, Mobasheri A: Anti-inflammatory and anti-catabolic effects of TENDOACTIVE(R) on human tenocytes in vitro. Histol Histopathol 2011, 26(9):1173-1185. Hankenson KD, Watkins BA, Schoenlein IA, Allen KG, Turek JJ: Omega-3 fatty acids enhance ligament fibroblast collagen formation in association with changes in interleukin-6 production. Proc Soc Exp Biol Med 2000, 223(1):88-95. Yoon JH, Halper J: Tendon proteoglycans: biochemistry and function. J Musculoskelet Neuronal Interact 2005, 5(1):22-34. Rees SG, Dent CM, Caterson B: Metabolism of proteoglycans in tendon. Scand J Med Sci Sports 2009, 19(4):470-478.

EP

22.

AC C

209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243

11

ACCEPTED MANUSCRIPT

Bullet Points- Nutritional Research May be Useful in Treating Tendon Injuries. Tendon Injuries Cause a Huge Amount of Pain, Disability, Medical Costs, and Suffering.

•

Tendon injuries are hard to treat

•

Relatively little is known about tendon biology as compared to muscle or bone biology.

•

Limited Research Suggests Nutritional Treatments May Be Useful for Tendon Healing

•

Amino acids, vitamins D&C, manganese, copper, and zinc may be useful for tendon healing.

AC C

EP

TE D

M AN U

SC

RI PT

•