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Elsevier Editorial System(tm) for Nutrition
Manuscript Draft
Manuscript Number: NUT-D-15-00641R1
Title: Nutritional Research May Be Useful in treating Tendon Injuries.
Article Type: Review
Keywords: Nutrition, Tendon, Tenocytes, Achilles tendon, rotator cuff,
Collagen, Proteoglycans, Vitamins C & E, Zinc, Manganese, Copper,
Leucine, Arginine, Glutamine
Corresponding Author: Dr. Luke Theodore Curtis, MD
Corresponding Author's Institution: Curtis Research
First Author: Luke Theodore Curtis, MD
Order of Authors: Luke Theodore Curtis, MD
Abstract: Tendon injures cause a huge amount of disability, pain, and
medical costs. However, relatively little is known about tendon biology
and healing. Many tendon related surgical procures are not very
successful and leave the patient with essentially a chronic injury. New
therapeutic approaches for tendon injury are needed. Preliminary
evidence suggests that various nutrients such as protein, amino acids
(leucine, arginine, glutamine), vitamins C+D, manganese, copper, zinc,
and phytochemicals may be useful to improve tendon growth and healing.
Much more research on nutrition and tendon health is needed. Since many
nutrients are required for tendon health, nutritional interventions
involving multiple nutrients may be more effective than single nutrient
strategies. In the future, ideal treatment regimens for tendon injuries
may include a multifaceted "bundle" of nutrition, drugs, biological
products, extracellular matrix therapies, exercise/ [physical therapy,
and possibly surgery.
11-12-2015
Dear Dr. Undurti Das
Thanks for your review and helpful comments from the reviewers. I have tried
to best address the reviewers questions in the new review paper submitted.
Where I made changes I mentioned them in the review document comments in
Word. My responses to the comments of the reviewers are listed below inside
the @@ @@.
Thanks for your time and editorial consideration. I hope you have space and
interest for this article. I would be happy to make more revisions if you wish. I
hope this short review will stimulate more clinical and research interest in
nutrition and tendon health.
Luke Curtis MD, MS, CIH
12570 Portland Avenue South #223
Burnsville, MN 55337 USA
H 952-513-7568
C 847-769-4768
LukeTCurtis@aol.com
Ms. Ref. No.: NUT-D-15-00641
Title: Nutritional Research May Be Useful in
treating Tendon Injuries.
Nutrition
Dear Dr. Curtis,
Your article
Nutritional Research May Be Useful in treating Tendon Injuries. has been
returned by our reviewers. In its present form, it cannot be accepted for
publication in Nutrition.
However, Nutrition would be willing to reconsider
Cover Letter
it for possible publication, if you feel you can fully address the reviewers'
comments. Please remember that we would have to send your revised
manuscript
back to the original referees and keep this time frame in mind when you
respond
to the critiques.
If you wish to have your manuscript reconsidered for
publication, please revise it and return it to this office by 2015-12-09
00:00:00.
For your guidance, reviewers' comments are appended
below.
Please provide along with your cover letter a list of your responses
to the reviewers' critiques and the changes you have made in your manuscript.
To submit a revision,
please go to http://ees.elsevier.com/nut/ and login as an Author. On your
Main
Menu page is a folder entitled "Submissions Needing Revision". You will find
your submission record there.
Your username is: LukeTCurtis@aol.com
If
you need to retrieve password details please go to:
http://ees.elsevier.com/nut/automail_query.asp
We look forward to hearing from you.
Yours
sincerely,
Undurti N. Das, M.D., FAMS, FRSC
Review
Editor
Nutrition
Reviewers' comments:
Reviewer #1: Major comments:
1.
The review article usually needs at least one figure or table for
illustration. @@ Good point. I have included a table that summarizes data on
which nutrients may be helpful in human, animal, cell culture studies. If you
think this table is redundant we could skip it. @@
2. There is no any keyword for the abstract. @@ I have added some keywords-
thanks for catching my error@@
Minor
comments:
1. There is no line number for the text. @@ Good idea- I added them. @@
2. There are a few
typographic errors in the last line on page 1 and the 14th line on page 5.
3. @@ Corrected- thank you @@
There is lack of journal names for reference # 7 and # 27. @@ Thanks sorry for
my silly errors@@
Reviewer #2:
This review attempts to highlight a paucity of human research regarding the
influence of nutrition on connective tissue healing. This review does highlight
the lack of human research by presenting almost exclusively animal studies;
however, does not make a strong case for urging clinicians to "consider
nutritional approaches in as a partial strategy in treating tendon problems" as
stated in the Purpose. It well known that not all animal research translates to
human research and there should be extensive human research before any
clinical
recommendations should be made. @@ I have included a statement in the
conclusions that “Most of the research on tendons and nutrition have dealt
with animal or cell culture studies which may or may not be representative of
the effects of nutrition and tendon health in humans.
@@
If you wish I could discuss this further.
Abstract
-change "procures" to
"procedures" @@ Corrected- thank you@@
-remove"[" symbol before "physical
therapy"
Introduction
Paragraph 1, Line 4-Please clarify the annual cost. It
is presented here in Euros but your research institute is located in the US, are
you speaking to the annual cost in the US or International? @@ Mentioned US$
cost of about US$$196 Billion)
Comment [LC1]: Additional testing
in humans is needed.
Methods
P1,
L5-Change "FDA. Gov" to "FDA.gov" @@Yes-thanks good catch@@
P1, L13-Provide exact number of research
articles and exact number of reviews (out of the approx. 110 total collected)
that were actually selected for citation based on your criteria
provided.
Nutrition and Tendon Growth and Healing
P1, L5-Please clarify
whether increases in tendon CSA were due to whey protein supplementation or
RT
or to both concurrently. @@ I mentioned concurrent whey protein and exercsise
P1, L6-Should say "grams per day" (CVhanged- thanks@@
P2, L2-Change
"intervention's" to "interventions" @@ Corrected@@
P2, L16-Pathway name is mTOR not TOR @@ Corrected @@
P2,
L19-Remove "bodyweight" as "mass" applies to both muscle and lean that you
are
referring to. @@ good catch@@
P2, L20-Replace "muscle-wasted" with "cachectic" as this is the
preferred term for disease-related muscle wasting @@ OK- although loss of
muscle mass is often a combination of cachectia and sarcopenia. @@
P3, L7-Replace "had" with
"with" @@ Fixed@@
Reviewer #1: Major comments:
1.
The review article usually needs at least one figure or table for
illustration. @@ Good point. I have included a table that summarizes data on
which nutrients may be helpful in human, animal, cell culture studies. If you
think this table is redundant we could skip it. @@
2. There is no any keyword for the abstract. @@ I have added some keywords-
thanks for catching my error@@
Minor
comments:
1. There is no line number for the text. @@ Good idea- I added them. @@
2. There are a few
typographic errors in the last line on page 1 and the 14th line on page 5.
3. @@ Corrected- thank you @@
There is lack of journal names for reference # 7 and # 27. @@ Thanks sorry for
my silly errors@@
Reviewer #2:
This review attempts to highlight a paucity of human research regarding the
influence of nutrition on connective tissue healing. This review does highlight
the lack of human research by presenting almost exclusively animal studies;
however, does not make a strong case for urging clinicians to "consider
nutritional approaches in as a partial strategy in treating tendon problems" as
stated in the Purpose. It well known that not all animal research translates to
human research and there should be extensive human research before any
clinical
recommendations should be made. @@ I have included a statement in the
conclusions that “Most of the research on tendons and nutrition have dealt
with animal or cell culture studies which may or may not be representative of
the effects of nutrition and tendon health in humans.
@@
If you wish I could discuss this further.
Abstract
-change "procures" to
"procedures" @@ Corrected- thank you@@
-remove"[" symbol before "physical
therapy"
Introduction
Paragraph 1, Line 4-Please clarify the annual cost. It
is presented here in Euros but your research institute is located in the US, are
Comment [LC1]: Additional testing
in humans is needed.
*Response to Reviewers
you speaking to the annual cost in the US or International? @@ Mentioned US$
cost of about US$$196 Billion)
Methods
P1,
L5-Change "FDA. Gov" to "FDA.gov" @@Yes-thanks good catch@@
P1, L13-Provide exact number of research
articles and exact number of reviews (out of the approx. 110 total collected)
that were actually selected for citation based on your criteria
provided.
Nutrition and Tendon Growth and Healing
P1, L5-Please clarify
whether increases in tendon CSA were due to whey protein supplementation or
RT
or to both concurrently. @@ I mentioned concurrent whey protein and exercsise
P1, L6-Should say "grams per day" (CVhanged- thanks@@
P2, L2-Change
"intervention's" to "interventions" @@ Corrected@@
P2, L16-Pathway name is mTOR not TOR @@ Corrected @@
P2,
L19-Remove "bodyweight" as "mass" applies to both muscle and lean that you
are
referring to. @@ good catch@@
P2, L20-Replace "muscle-wasted" with "cachectic" as this is the
preferred term for disease-related muscle wasting @@ OK- although loss of
muscle mass is often a combination of cachectia and sarcopenia. @@
P3, L7-Replace "had" with
"with" @@ Fixed@@
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.
*Highlights (for review)
1
1
NUTRITIONAL RESEARCH MAY BE USEFUL IN TREATING TENDON INJURIES 2
Luke Curtis, MD, MS, Curtis Research, 12570 Portland Avenue S #223, 3
Burnsville, MN 55337, USA LukeTCurtis@aol.com 4
5
Abstract 6
Tendon injures cause a huge amount of disability, pain, and medical costs. 7
However, relatively little is known about tendon biology and healing. Many 8
tendon related surgical procedures are not very successful and leave the 9
patient with essentially a chronic injury. New therapeutic approaches for 10
tendon injury are needed. Preliminary evidence suggests that various 11
nutrients such as protein, amino acids (leucine, arginine, glutamine), vitamins 12
C+D, manganese, copper, zinc, and phytochemicals may be useful to improve 13
tendon growth and healing. 14
Much more research on nutrition and tendon health is needed. Since many 15
nutrients are required for tendon health, nutritional interventions involving 16
multiple nutrients may be more effective than single nutrient strategies. In the 17
future, ideal treatment regimens for tendon injuries may include a multifaceted 18
“bundle” of nutrition, drugs, biological products, extracellular matrix therapies, 19
exercise/ physical therapy, and possibly surgery. 20
Comment [LC1]: Corrected
*Manuscript
Click here to view linked References
2
21
Keywords: tendon, Achilles tendon, rotator cuff, tenocytes, vitamin C, amino 22
acids, manganese, copper, zinc, phytochemicals. 23
24
Introduction 25
Tendon injuries cause a great deal of pain, disability, and medical & economic 26
costs [1, 2]. The exact prevalence of tendon injuries is unknown, but it is 27
estimated that worldwide over 30 million patients have tendon-related surgical 28
procedures annually at a medical cost of over €140 billion per year (about US$ 29
196 Billion) [3]. Surgical repairs for tendon injuries require a long and painful 30
recuperation and are often not very successful, leaving the patient with 31
essentially a permanent injury [3-7]. Clearly, better treatments for tendon 32
injuries are needed. 33
Tendon healing is generally a very slow and incomplete process [1, 6-8]. Use of 34
biological and biomaterial approaches, such as use of platelet rich plasma, 35
extracellular matrix (ECM)/ scaffold treatments, regulation of growth factors 36
and cytokines, and stem cell based approaches, potentially offer promise in 37
speeding up and improving repair of torn or otherwise damaged tendons [1, 3, 38
5, 8, 9]. There is a dearth of both basic and applied tendon research, and our 39
basic understanding of tendon biology lags far behind that of muscle or bone 40
[1, 2, 6, 7] . 41
Comment [LC2]: Added this
3
The purpose of this short review is twofold: 1) To describe existing research on 42
nutrition and tendon health/ healing and: 2) To stimulate interest in clinicians 43
and researchers to consider nutritional approaches as a partial strategy in 44
treating tendon problems. 45
46
Methods 47
About 110 research and review articles were collected for information about for 48
studies relating tendons with nutrition and related topics. Animal and cell 49
culture studies were included as in vivo studies of nutrition and tendons in 50
humans is currently sparse. Various Medical Database were searched for 51
articles include PubMed, Google and Google Scholar, FDA.Gov, and clinical 52
trials.gov. No time restriction was placed on the search. Searched terms 53
included a variety of tendon related terms including tendon, tendonitis, tendon 54
tears, Achilles tendon, rotator cuff, patellar tendon, tenocytes, collagen, leucine 55
rich proteins, and proteoglycans. Many nutritional related terms were also 56
used including calories, omega 3 fats, protein, amino acids (such as leucine, 57
glutamine, arginine and taurine), fruits, vegetables, phytochemicals, vitamins 58
(including all of the various vitamins), minerals (Ca, Mg, Zn, Cu, Mn, Fe, Mo, 59
Si) and coenzyme Q10. A total of 33 articles were selected for citing in this 60
review if they were deemed to have relevance in exploring relationships between 61
tendons and nutrition. 62
Comment [LC3]: Corrected
Comment [LC4]: Added0 change if
you add more references
4
63
Nutrition and Tendon Growth and Healing 64
Nutrition may play a major role in tendon healing, although research has been 65
sparse to date. The majority of work to date has involved animals or cultured 66
human cells, although there are a few clinical human studies. Some animal 67
and human studies report significantly better tendon growth or collagen 68
synthesis following various nutritional interventions. Supplementation with 69
19.5 grams per day of whey protein was found to significantly increase patellar 70
and quadricep tendon cross sectional area in a group of 22 young men 71
concurrently in an exercise program [10]. Vitamin C is necessary for the 72
enzymatic synthesis of both collagen proteins and several proteoglycans found 73
in tendons [11]. Vitamin C is also a transcriptional promoter of collagen 74
synthesis [12]. A rat study reported that high dose oral vitamin C 75
supplementation significantly accelerated healing of ruptured Achilles tendons 76
[12]. Another rat study reported that a vitamin D deficient diet significantly 77
slowed healing and buildup of biomechanical strength of the rotator cuff [13]. 78
High dose oral glucosamine/ chondroitin sulphate was found to significantly 79
accelerate tendon to bone healing in rabbits [14]. Taurine injected at the 80
tendon repair site was found to significantly improve load strength in rats with 81
repaired Achilles tendons [15]. Deficiencies of biotin, folate, or manganese 82
were found to significantly increase tenosynovitis in reovirus infected chickens 83
[16].
84
Comment [LC5]: Added
Comment [LC6]: Added
5
Since collagen forms the major extracellular protein in tendons, muscle, and 85
ligaments [1, 11, 17] dietary interventions to increase collagen synthesis 86
and/or protein synthesis in general may be helpful in rebuilding tendons. 87
Such dietary interventions might include providing sufficient overall calories/ 88
protein and supplementation with such nutrients as trace minerals and/or 89
amino acids. Numerous animal and human studies have reported that diets 90
deficient in protein and/or calories lead to significantly less collagen 91
production [11]. Many trace minerals such as zinc, copper, and manganese 92
play a key role in collagen metabolism, and nutritional deficiencies in these 93
minerals have been linked to poorer collagen synthesis [18, 19]. Amino acid 94
supplementation with glutamine, arginine, and branched chained amino acids 95
(leucine, isoleucine, and valine) was found to significantly increase skin 96
collagen synthesis in UV-irradiated mice [20]. Various studies have reported 97
that dietary consumption of leucine or its metabolite ß-hydroxy-ß-98
methylbutyrate (HMB) simulate protein synthesis via signaling pathways 99
involving mmTOR(mammalian target of rapamycin) in a dose–response manner 100
[21]. Other studies have reported that oral supplementation of mixtures of 101
HMB, glutamine, and arginine can significantly increase muscle and/or lean 102
mass in a wide variety of patients including the elderly [22], cachectic HIV 103
patients [23], and muscle-wasted cancer patients [24]. . 104
Since many nutrients are involved with tendon and collagen metabolism, 105
nutritional interventions employing multiple nutrients may yield better results 106
Comment [LC7]: Change β to beta??
Comment [LC8]: Add m thanks for
the correction
Comment [LC9]: Removed
bodyweight.
Comment [LC10]: Changed
6
as compared to studies employing only one nutrient. A human study of 90 107
patients with rotator cuff surgery reported that the use of a multifaceted 108
Tenosan® supplement containing 1 gram of arginine l-alpha- ketoglutarate, 1.1 109
grams methylsulfonylmethane, 600 mg hydrolyzed collagen, 120 mg. vitamin 110
C, and 100 mg bromelain daily was associated with significantly better repair 111
integrity at final follow-up [25]. A human study of patients with insertional 112
Achilles tendinopathy treated 32 patients with the Tenosan supplement 113
(mentioned above) and 32 patients with placebo. All patients also underwent 3 114
courses of extracorporeal shockwave therapy. After 6 months pain was 115
significantly reduced and patient satisfaction was significantly increased in the 116
Tenosan treated patients as compared to the placebo treated patients [26]. 117
In vitro studies also suggest that various nutrients like phytochemicals from 118
plants or Ω-3 fats may be useful for tendon repair and health. Cyanidin is a 119
colored pigment found in many fruits and vegetables including red cabbage, 120
cherries, bilberries, serviceberries, red and black grapes, blueberries, and 121
blackberries. Cyanidin (100 µg/ml) was found to inhibit autophagic cell death 122
in human rotator cuff tenoblasts [27]. Curcumin (a diarylheptanoid found in 123
turmeric) was found to significantly reduce inflammation in human tenocytes 124
[28]. A study of Achilles tendons from orofloxicin treated rats reported that 125
degenerative changes were significantly more common in rats fed a magnesium 126
deficient diet as compared to a magnesium sufficient diet [29]. A supplement 127
containing vitamin C, collagen type 1, manganese, and mucopolysaccharides 128
Comment [LC11]: Thanks for
catching my error.
7
showed significant anti-inflammatory and anti-catabolic effects of human 129
tenocytes in vitro [30] . The Ω-3 fatty acid EPA (eicospentaenoic acid) was 130
found to enhance collagen formation in cultured human medial collateral 131
ligament fibroblasts [31] . 132
Proteoglycans are proteins found in the tendons’ extracellular matrix (ECM) 133
which play a critical role in the function and structure of tendons. The two 134
main classes of tendon proteoglycans include: 1) small leucine rich 135
proteoglycans (SLRPs) including decorin, fibromodulin, lumican, and biglycan; 136
137
these proteins bind to collagen fibrils and 2) large molecular proteoglycans 138
such as aggrecan and versican which are associated with tendon loading and 139
mobilization [32, 33]. Perhaps nutritional interventions with leucine and/or 140
other nutrients may improve synthesis and function of tendon proteoglycans. 141
Understanding of the relationships between nutrition and tendon proteoglycans 142
is lacking and major research in this area is clearly needed. 143
SUMMARY 144
Table 1 below summarizes various human, animal and cell culture studies 145
which suggest that various nutrients may be helpful to tendon health, growth 146
or repair. 147
148
Comment [LC12]: Perhaps a
summary table would be good to
include here. If no- it could easily
beremoved.{Farup, 2014 #153}
8
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.
Nutrient
Human
Studies
Animal Studies-
Mammals or Birds
Cell Culture
Studies or
Animal
Organs
Whey Protein
[10]
Vitamin C
[12]
Vitamin D
[13]
Glucosamine /
Chondroitin Sulfate
[14]
Taurine
[15]
Biotin, Folate, Manganese
[16]
Calories
[11]
[11]
Protein
[11]
[11]
Glutamine, Arginine,
Leucine, Isoleucine,
Valine
[20]
Tenosan®. 1 gram of
arginine l-alpha-
ketoglutarate, 1.1 grams
methylsulfonylmethane,
600 mg hydrolyzed
collagen, 120 mg. vitamin
C, and 100 mg bromelain
daily.
[25, 26]
Cyanadin (Phytochemical
found in many fruits/
vegetables)
[27]
Curcumin
[28]
Magnesium
[29]
Vitamin C, Collagen Type
[30]
9
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.
Nutrient
Human
Studies
Animal Studies-
Mammals or Birds
Cell Culture
Studies or
Animal
Organs
1, Manganese, &
Mucopolysaccharides
EPA or Eicospentaenoic
Acid (Ω-3 Fatty Acid)
[31]
149
CONCLUSION 150
Much more research and clinical attention is needed to develop better 151
treatment strategies for torn or damaged tendons. Most of the research on 152
tendons and nutrition have dealt with animal or cell culture studies which may 153
or may not be representative of the effects of nutrition and tendon health in 154
humans. Additional research on human nutrition and tendon health/repair is 155
needed. Most nutritional interventions interventions are fairly inexpensive and 156
have a low risk of side effects. A “bundle” of multiple interventions may be 157
needed for optimal tendon growth and healing. In the future, ideal treatment 158
for tendon injuries may include a multifaceted program of good nutrition/ 159
supplements, drugs, biological products/ stem cells, extracellular matrix/ 160
scaffold therapies, exercise/ physical therapy, and possibly surgery. 161
REFERENCES 162
Comment [LC13]: Additional testing
in humans is needed.
10
163
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11
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286(32):28556-28566. 231
29. Shakibaei M PK, Schwabe R, Vormann J, Stahlman R: Ultrastructure of Achilles tendomn of rats 232
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