Collagen

• Collagen is the most abundant protein within the body, residing in the extracellular matrix (ECM) of several tissues including skin, bone, ligaments and tendons.¹ It is unique in that it forms as a triple helical structure, resulting in a rigid and durable tissue, which provides structure and support to the body, as well as playing a role in locomotion.² To date, there are 28 different types of collagen known which are composed of polypeptide chains.³
• Within bone, muscle and connective tissue, Type 1 collagen predominates, consisting of non-essential amino acids (NEAAs) including glycine, proline, hydroxyproline and hydroxylysine.⁴ The specific role of each of these AAs and/or peptides after the consumption of collagen is still being explored.

• Plasma levels of glycine decline post exercise, potentially due to increased utilisation. This suggests an increased need for glycine while collagen synthesis is elevated post exercise.⁵ It has been hypothesized that under circumstances of high demand such as a heavy training stimulus, dietary collagen may be of potential benefit.
• The addition of ascorbic acid and proline to cell culture growth media), results in an increased collagen content and improvement to mechanical properties⁶. This suggests both are important nutrients for the synthesis of collagen in connective tissue. However, whether intake beyond dietary sufficiency is required in vivo is yet to be determined.
  • Although AAs derived from the consumption of diary protein (casein), including proline are incorporated into intramuscular connective tissue after a bout of resistance training, this does not result in a further increase of intramuscular connective tissue protein synthesis rates, compared to when a placebo is consumed. This may be due to the low glycine content of casein compared to collagen proteins.⁵
  • Inflammation results in the disorganisation of collagen fibrils in the ECM, and has been proposed to lead to conditions such as tendinopathy.⁶ Glycine has been shown to inhibit inflammatory cell activation⁷, and therefore may be able to exert a beneficial effect in inflammatory conditions. The administration of glycine results in an improvement in the biochemical and biomechanical properties of an inflamed rat tendon⁸, and restores the anabolic response of muscle tissue to leucine under acute inflammatory conditions.⁹
  • Plasma di and tri peptide amino acids of hydroxyproline available post the ingestion of collagen proteins appear to trigger a range of signalling responses in the human body. How this translates into functional outcomes of enhanced collagen synthesis or improved connective tissue health in vivo is still unclear.¹⁰

• Hydrolysed collagen is a form of collagen that has undergone enzymatic hydrolysis to reduce its’ gelling properties to enable it to be easily mixed with water, and ingested.¹¹ Meanwhile, specific collagen peptide formulations have been developed to optimise the amount of di and tri AA peptides of hydroxyproline with different molecular weights. Such formulations are claimed to have increased bioavailability,and exert additional biological functions specific to the target tissues.^12-15 However, it should be noted that there does not appear to be significant differences in the bioavailability of key AAs after the consumption of different forms of collagen.¹⁶
• The consumption of collagen results in a transient increase of circulating NEAA within the blood, peaking between 40-60 minutes after consumption.^{16, 17} However, there appears to be some individual variability with the availability of AAs after the consumption of collagen protein. Variability in amino acid appearance between subjects and interventions likely influenced by body weight, and possible polymorphisms of transporters and enzymes, which is potentially linked to habitual dietary intake of collagen sources.¹⁸ Further research is required to determine these individual factors.

• Although bone collagen is responsive to feeding in the absence of exercise¹⁹, collagen in musculoskeletal tissue is non-responsive to feeding in the absence of exercise.²⁰ Exercise is necessary to “switch-on” synthetic machinery in muscle and connective tissue ²¹, and may also increase the delivery of specific AAs when their availability is increased (i.e. after the consumption of protein sources), particularly in dense connective tissues which are otherwise poorly vascularised.²² Further, as it has been shown that proline is integrated into muscle collagen when dairy protein is ingested post exercise⁵, it is possible that protein to support muscle recovery/repair may be better consumed post exercise.
• A recent study has shown that serum obtained from individuals after the consumption of dietary collagen (gelatin) resulted in an increased collagen content, and improved tissue mechanics of an engineered ligament. Meanwhile, an in vitro arm of the same study illustrated an increased availability of collagen specific AAs within the blood, and an increase in a blood marker of collagen synthesis (Procollagen type I Intact N-Terminal) after collagen was consumed 1h prior to a 6-minute skipping exercise.¹⁷ This suggests that the increased availability of collagen specific AAs and/or peptides in combination with exercise may result in an increased collagen synthesis within connective tissue.
• Although gelatin (a partially hydrolysed form of collagen utilised predominantly in food manufacturing) has been utilised in formative research exploring the impact of collagen intake on the synthesis of collagen, it is not considered to be palatable in its raw form to consume mixed in water due to collagens gelling properties, and therefore alternative formulations may be better tolerated. Incorporation of gelatin into food sources or forms should not influence its AA availability.

• Although in vivo research remains limited, it has been suggested that collagen supplementation may assist in the prevention and/or treatment of muscle, cartilage, connective and bone tissue injury and/or degenerative disorders.²³ A recent case study has shown that the combination of a rehabilitation protocol, including exercise and supplemental collagen protein may help hastened return to play.²⁴ Meanwhile, collagen specific peptides in conjunction with calf-strengthening exercises has been shown to increase functionality and reduce pain during tendinopathy.¹⁴ Other investigations have shown a reduction in subjective joint pain²⁵, plus decreased inflammation and muscle damage after strenuous exercise.²⁶
• Collectively, collagen supplementation, and/or the increased availability of AA which predominate in collagen may be beneficial for both the prevention and treatment of injury and degenerative bone and connective tissue disorders. However, the research remains within its’ infancy and more long-term studies are required to determine optimal doses, formulations and contra-indications for use. Thus, the use of collagen as part of an injury-prevention or management protocol should be considered carefully and should be used as an adjunct, not a replacement for traditional well-established processes.

• Hydrolysed collagen and collagen peptide formulas are available in the form of pills or powder, and can be derived from porcine, bovine or marine animals. The differences in the AA content of various animal and human collagen sources are presented in Table 1. Recent research has shown there is no significant difference in plasma availability of key AAs after the consumption of various collagen protein sources.¹⁶ Therefore, the source of collagen is unlikely to influence its’ effectiveness.
• Collagen in the form of gelatin is considered as a food product, and therefore, does not require batch-testing for use in athletes., Where access and/or budget is a consideration, gelatin may be a preferential option, especially if made into more palatable jellies or jubes.
• Some collagen formulations include ascorbic acid, due to its role as a cofactor in collagen synthesis.¹⁷ However, whether there is benefit beyond dietary sufficiency of ascorbic acid for collagen synthesis remains to be determined.
• Unfortunately, Australian food databases do not contain information on the collagen content of foodstuffs (measured as hydroxyproline), and therefore, it is not possible to determine collagen intake through food sources. Further, research has indicated that the AA content of collagen in bone broth, is too variable to use as a therapeutic source of collagen.²⁷

Table 1: Amino acid composition of the 5 major mammalian collagens and gelatin

Amounts given in grams per 100 grams of dry ash-free Protein. Adapted from.²⁸

• Although recent research utilised 15 grams of gelatin, this was due to the requirement to blind participants from the intervention. Other studies have shown an increased availability of AAs after the intake of up to 20-25 grams of collagen, Consequentially a minimum of 20 grams is likely optimal for increased AA availability around exercise in a timely manner16, ²⁹. It is possible that similar to other types of protein, a dose response relationship exists, however, this requires further research.
• Although more research is required to confirm the use of hydrolysed collagen and/or specific collagen peptide formulas for a range of scenarios and/or target tissues, it may be beneficial in the following situations as part of an overall injury management and/or prevention plan (in conjunction to well established methods):
• As mentioned, Vitamin C (ascorbic acid) is important as a cofactor in collagen synthesis, so the diet must be sufficient in Vit C.

Consumed daily:

• In conjunction with specific exercise to help pain management for inflammatory conditions such as tendinitis.
• To help reduce activity-related joint pain.
• For the treatment/prevention of degenerative diseases, such as osteoarthritis.
• To assist in bone strength in order to reduce fracture risk.

Consumed 40-60 minutes prior to exercise to:

• Help to support collagen turnover in connective tissue by providing an increased availability of AAs during periods of increased turnover, particularly when the body is unable to keep up with demand and/or when total protein intake is suboptimal, such as during a high training stimulus.
• Help support tissue integrity for those with previous connective tissue injury.
• Support the repair of various tissues, including bone, skin and ligaments/tendons during rehabilitation.

Consumed immediately post exercise in order to:

• Support the repair/recovery of muscle tissue, and potentially reduce delayed onset muscle soreness.

There is insufficient evidence to support the use of vegetarian/vegan alternatives

Collagen protein is animal-derived and therefore may not be appropriate for vegetarian/vegan athletes. Although there are vegan/vegetarian products available that are claimed to mimic animal sources of collagen, if peptides specific to animal proteins are proved to have specific biological activity, then vegetarian/vegan options may be viewed as less effective. More work is required to determine the AA availability and effectiveness of vegan collagen alternatives.

Potential individual variability of availability of AAs that may support collagen synthesis

As per any supplement, an individual approach should be considered. The individual availability of AAs proposed to increase collagen synthesis may be impacted by the following: habitual intake of protein, particularly collagenous proteins which may lead to differences in baseline AAs availability and/or reduced capacity to digest specific AA; training load in which the requirement of AAs such as glycine are conditionally increased; an individual’s body mass, leading to increased utilisation; the use of AAs in other processes such as bone remodelling.

Addition of ascorbic acid and its’ impact on interference with physiological adaptation

Chronic Vitamin C supplementation may impair physiological adaptation (see Vitamin C). Adequacy of dietary derived Vitamin C should be confirmed.

Religions requiring Halaal products

Halal certified collagen protein supplements are commercially available.

Gatorade Sports Science Institute www.gssiweb.org, opens in a new tab

Supplement safety information www.sportintegrity.gov.au/what-we-do/anti-doping/supplements-sport, opens in a new tab

1. Kadler, K., Holmes, D., Trotter, J., & Chapman, J. (1996). Collagen fibril formation. Biochem J, 316 ( Pt 1), 1-11.
2. Myllyharju, J., & Kivirikko, K. I. (2009). Collagens and collagen-related diseases. Annals of Medicine, 33(1), 7-21.
3. Shoulders, M. D., & Raines, R. T. (2009). Collagen structure and stability. Annu Rev Biochem, 78, 929-958.
4. Li, P., & Wu, G. (2018). Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids, 50(1), 29-38.
5. Trommelen, J., Holwerda, A. M., Senden, J. M., Goessens, J. P. B., J, V. A. N. K., Gijsen, A. P., . . . LJC, V. A. N. L. (2020). Casein Ingestion Does Not Increase Muscle Connective Tissue Protein Synthesis Rates. Med Sci Sports Exerc, 52(9), 1983-1991.
6. Paxton, J. Z., Grover, L. M., & Baar, K. (2010). Engineering an in vitro model of a functional ligament from bone to bone. Tissue Eng Part A, 16(11), 3515-3525.
7. Trommelen, J., Holwerda, A. M., Senden, J. M., Goessens, J. P. B., J, V. A. N. K., Gijsen, A. P., . . . LJC, V. A. N. L. (2020). Casein Ingestion Does Not Increase Muscle Connective Tissue Protein Synthesis Rates. Med Sci Sports Exerc, 52(9), 1983-1991.
8. Dunstan, R. H., Macdonald, M. M., Murphy, G. R., Thorn, B., & Roberts, T. K. (2019). Modelling of protein turnover provides insight for metabolic demands on those specific amino acids utilised at disproportionately faster rates than other amino acids. Amino Acids, 51(6), 945-959.
9. Lipman, K., Wang, C., Ting, K., Soo, C., & Zheng, Z. (2018). Tendinopathy: injury, repair, and current exploration. Drug Des Devel Ther, 12, 591-603.
10. Zhong, Z., Wheeler, M. D., Li, X., Froh, M., Schemmer, P., Yin, M., . . . Lemasters, J. J. (2003). L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care, 6(2), 229-240.
11. Vieira, C. P., De Oliveira, L. P., Da Re Guerra, F., Dos Santos De Almeida, M., Marcondes, M. C., & Pimentel, E. R. (2015). Glycine improves biochemical and biomechanical properties following inflammation of the achilles tendon. Anat Rec (Hoboken), 298(3), 538-545.
12. Ham, D. J., Caldow, M. K., Chhen, V., Chee, A., Wang, X., Proud, C. G., . . . Koopman, R. (2016). Glycine restores the anabolic response to leucine in a mouse model of acute inflammation. Am J Physiol Endocrinol Metab, 310(11), E970-981.
13. Oertzen-Hagemann, V., Kirmse, M., Eggers, B., Pfeiffer, K., Marcus, K., de Marees, M., & Platen, P. (2019). Effects of 12 Weeks of Hypertrophy Resistance Exercise Training Combined with Collagen Peptide Supplementation on the Skeletal Muscle Proteome in Recreationally Active Men. Nutrients, 11(5).
14. Leon-Lopez, A., Morales-Penaloza, A., Martinez-Juarez, V. M., Vargas-Torres, A., Zeugolis, D. I., & Aguirre-Alvarez, G. (2019). Hydrolyzed Collagen-Sources and Applications. Molecules, 24(22).
15. Edgar, S., Hopley, B., Genovese, L., Sibilla, S., Laight, D., & Shute, J. (2018). Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. Sci Rep, 8(1), 10474.
16. Oesser, S., Schulze, C. H., Zdzieblik, D., & König, D. (2016). Efficacy of specific bioactive collagen peptides in the treatment of joint pain. Osteoarthritis and Cartilage, 24, S189.
17. Praet, S. F. E., Purdam, C. R., Welvaert, M., Vlahovich, N., Lovell, G., Burke, L. M., . . . Waddington, G. (2019). Oral Supplementation of Specific Collagen Peptides Combined with Calf-Strengthening Exercises Enhances Function and Reduces Pain in Achilles Tendinopathy Patients. Nutrients, 11(1).
18. Schunck, M., & Oesser, S. (2013). Specific collagen peptides benefit the biosynthesis of matrix molecules of tendons and ligaments. Journal of the International Society of Sports Nutrition, 10(Suppl 1), P23.
19. Alcock, R. D., Shaw, G. C., Tee, N., & Burke, L. M. (2019). Plasma Amino Acid Concentrations After the Ingestion of Dairy and Collagen Proteins, in Healthy Active Males. Front Nutr, 6, 163.
20. Shaw, G., Lee-Barthel, A., Ross, M. L., Wang, B., & Baar, K. (2017). Vitamin C-enriched gelatin supplementation before intermittent activity augments collagen synthesis. Am J Clin Nutr, 105(1), 136-143.
21. Lis, D. M., & Baar, K. (2019). Effects of Different Vitamin C-Enriched Collagen Derivatives on Collagen Synthesis. Int J Sport Nutr Exerc Metab, 29(5), 526-531.
22. Babraj, J. A., Smith, K., Cuthbertson, D. J., Rickhuss, P., Dorling, J. S., & Rennie, M. J. (2005b). Human bone collagen synthesis is a rapid, nutritionally modulated process. J Bone Miner Res, 20(6), 930-937.
23. Babraj, J. A., Cuthbertson, D. J., Smith, K., Langberg, H., Miller, B., Krogsgaard, M. R., . . . Rennie, M. J. (2005a). Collagen synthesis in human musculoskeletal tissues and skin. Am J Physiol Endocrinol Metab, 289(5), E864-869.
24. Kjaer, M., Jorgensen, N. R., Heinemeier, K., & Magnusson, S. P. (2015). Exercise and Regulation of Bone and Collagen Tissue Biology. Prog Mol Biol Transl Sci, 135, 259-291.
25. Tempfer, H., & Traweger, A. (2015). Tendon Vasculature in Health and Disease. Front Physiol, 6, 330.
26. Close, G. L., Sale, C., Baar, K., & Bermon, S. (2019). Nutrition for the Prevention and Treatment of Injuries in Track and Field Athletes. International Journal of Sport Nutrition and Exercise Metabolism, 29(2), 189-197.
27. Shaw, G., Serpell, B., & Baar, K. (2019). Rehabilitation and nutrition protocols for optimising return to play from traditional ACL reconstruction in elite rugby union players: A case study. J Sports Sci, 37(15), 1794-1803.
28. Clark, K. L., Sebastianelli, W., Flechsenhar, K. R., Aukermann, D. F., Meza, F., Millard, R. L., . . . Albert, A. (2008). 24-Week study on the use of collagen hydrolysate as a dietary supplement in athletes with activity-related joint pain. Curr Med Res Opin, 24(5), 1485-1496.
29. Clifford, T., Ventress, M., Allerton, D. M., Stansfield, S., Tang, J. C. Y., Fraser, W. D., . . . Stevenson, E. (2019). The effects of collagen peptides on muscle damage, inflammation and bone turnover following exercise: a randomized, controlled trial. Amino Acids, 51(4), 691-704.
30. Alcock, R. D., Shaw, G. C., & Burke, L. M. (2018). Bone Broth Unlikely to Provide Reliable Concentrations of Collagen Precursors Compared With Supplemental Sources of Collagen Used in Collagen Research. Int J Sport Nutr Exerc Metab, 0(0), 1-8.
31. Eastoe, J. E. (1955). The amino acid composition of mammalian collagen and gelatin. Biochem J, 61(4), 589-600.
32. Iwai, K., Hasegawa, T., Taguchi, Y., Morimatsu, F., Sato, K., Nakamura, Y., . . . Ohtsuki, K. (2005). Identification of food-derived collagen peptides in human blood after oral ingestion of gelatin hydrolysates. J Agric Food Chem, 53(16), 6531-6536.