Biomarkers vs. Outcomes: How to Read Muscle-Peptide Research

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Biomarkers vs. Outcomes: How to Read Muscle-Peptide Research

One of the areas where you can find a lot of confident statements is around muscle peptides. Many products talk about using muscle peptides such as short-chained amino acid sequences to build or recover muscle. However, many of these claims are based on changes in lab results, or rat studies, rather than human muscle changes.

This article isn’t here to recommend or rank any of these peptides. Instead, we wanted to give you some clarity into how you can differentiate between a biomarker and outcome and what the actual evidence shows.

Why aren’t all peptides the same?

A peptide is a short-chain of amino acids. This can mean lots of different types of molecules. When looking at muscle, there are at least four categories of peptides:

• Nutritional – Amino acid rich sources such as dietary protein and collagen hydrolysates.
• Growth Hormone Secretagogues – Molecules such as GHRH analogs and ghrelin receptor agonists stimulate the pituitary to release Growth Hormone (GH) which in turn stimulates Insulin Like Growth Factor 1 (IGF-1).
• Growth Factor – IGF-1 analogs and Mechano Growth Factor (MGF). These target receptors in muscle tissue.
• Muscle Recovery – Compounds such as BPC-157 and fragments of Thymosin Beta-4. These are being studied for their effects on cell migration and tissue recovery.

These act through different mechanisms. Meaning that there is no transferability of evidence. For example, just because there is good evidence for collagen peptides doesn’t mean there will be for a growth factor analog.

Biomarker or Outcome?

A biomarker is something measurable in the body that is thought to relate to a specific outcome. These could be things like GH in blood, IGF-1 in serum, or some protein synthesis marker. An outcome would be the actual change in muscle mass (body composition scan), strength (standardized test) or function.

Biomarkers are useful as it shows that the compound is having some biological activity. The problem starts when a rise in a biomarker is presented as proof of the outcome. Not everything in biology works in a straight line.

The growth hormone axis is a good example. There are many human studies that show GH releasing compounds cause an increase in GH and IGF-1. One clinical trial looked at the long acting GHRH analog CJC-1295 and found that after a single dose, GH and IGF-1 levels remained elevated for several days in healthy adults (Teichman et al., 2006). While this is useful pharmacology evidence, muscle mass or strength wasn’t measured.

However, looking at outcomes:

• An oral ghrelin receptor agonist, MK-677 (not a peptide), was given to 65 healthy older adults for 1-2 years in a randomized trial. The study showed an increase in fat free mass (~1.1kg) compared to placebo. However, no improvements were seen in strength or function (Nass et al., 2008).
• A systematic review looking at 31 studies of recombinant GH in older healthy adults found increased lean mass, reduced fat mass but no proven improvements in strength. It also found increased incidence of soft tissue edema, joint pain and glucose effects (Liu et al., 2007).

So although there was an increase in the biomarker, there were some changes in lean mass but no improvements in the main outcome of interest (strength).

What is the actual evidence for muscle peptides?

Interestingly, when looking at muscle peptides in different models, the strongest evidence in humans is for nutritional peptides.

• Dietary Protein – A meta-analysis of 49 randomized controlled trials (n=1863) found that protein supplementation increased fat free mass and strength slightly more than resistance training alone (Morton et al., 2018).
• Collagen Peptides – A randomized trial with 53 older men with sarcopenia found that collagen peptides increased fat free mass and strength more than the placebo group during resistance training (Zdzieblik et al., 2015). More recently a trial with 77 premenopausal women found a similar trend (Jendricke et al., 2019).

Both found that there were only small increases and that they weren’t standalone but combined with structured exercise.

Preclinical Evidence

Much of the discussion around muscle peptides revolves around molecules which have only been tested in animals or in vitro.

IGF-1 LR3 is an engineered IGF-1 analog. It is designed to bind poorly to IGF-binding proteins in the blood. In rat studies it has shown to be ~3x more potent than native IGF-1 (Tomas et al., 1996). In vitro it stimulates muscle progenitor cell growth. It is commonly used as a supplement in laboratory cell culture. However, there aren’t any controlled human trials.

Mechano Growth Factor (MGF) is a splice variant of IGF-1 which is produced in muscle after mechanical stress. In rodent studies it has been shown to be expressed prior to satellite cell activation (stem cells involved in muscle repair and hypertrophy) (Goldspink, 2005). However, whether synthetic or modified versions will cause this in a live system over time hasn’t been tested in controlled studies.

BPC-157 has been studied in rats with transected and crushed muscles. It has been associated with faster functional and tissue recovery (Staresinic et al., 2006; Novinscak et al., 2008). In vitro it has been shown to increase outgrowth and migration of tendon cells (Chang et al., 2011). However, this is around muscle repair and not muscle growth. Limited human studies have since been reported, but they involve very small numbers of participants and do not establish that BPC-157 improves muscle growth, repair, strength or function in humans.

Thymosin Beta-4 is secreted at sites of muscle damage and attracts muscle progenitor cells in mice (Tokura et al., 2011). Human studies of the full protein have only looked at skin wounds and not skeletal muscle.

While preclinical evidence is useful for generating hypotheses and understanding mechanisms, it is only the start of a question.

5 Questions to ask yourself

When looking at a summary of a study, article or product, ask yourself:

1. What model was used? There are 3 levels of evidence. Cell based studies, animal studies and human studies. Many of the claims are based on the first two.
2. What was measured? An increase in GH or IGF-1 is a biomarker. Lean mass in body composition scans is closer to an outcome. Strength and function are often not measured.
3. Was there a control and randomization? Without this it can be difficult to know whether the compound is causing the effect or if it is due to training, diet or chance.
4. Who was it tested on? Older adults with low GH, patients with a specific medical condition and lab rats are not the same as healthy trained adults.
5. Is it the same molecule? Just because there is data for one type of molecule doesn’t mean it will apply to modified versions, fragments or similar molecules with similar names.

See this overview of peptides for muscle building for a molecule by molecule breakdown of what evidence there is and what models were used in the studies.

Regulation & Sport

None of the injectable peptides mentioned above are approved for muscle building. Several of the peptides are prohibited in competitive sport under the World Anti-Doping Agency rules, including substances covered by the S2 class, while BPC-157 is prohibited separately as a non-approved substance. Many are sold as research chemicals and are not approved for human use. Companies like Generic Peptides publish certificates of analysis for their research chemicals. However, a certificate of analysis provides information about the tested sample; it does not establish that a compound is safe or effective for use in people.

Summary

Muscle peptides are a great example of how to critically analyze scientific information. The strongest evidence in humans is for a well known combination of resistance training and sufficient protein intake. Collagen peptides showed some small additional effects in some trials. The hormonal peptides reliably cause changes in biomarkers but haven’t shown any clear improvements in strength in the groups studied. The growth factor and muscle repair peptides are still in preclinical stages.

Often, asking ‘What model was it in? What was measured?’ is enough to tell a promising mechanism from a proven result.

References

1. Morton RW, et al. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018;52(6):376–384. PMID 28698222.
2. Zdzieblik D, et al. Collagen peptide supplementation in combination with resistance training improves body composition and increases muscle strength in elderly sarcopenic men. Br J Nutr. 2015;114(8):1237–1245. PMID 26353786.
3. Jendricke P, et al. Specific collagen peptides in combination with resistance training improve body composition and regional muscle strength in premenopausal women. Nutrients. 2019;11(4):892. PMID 31010031.
4. Teichman SL, et al. Prolonged stimulation of growth hormone and IGF-I secretion by CJC-1295 in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799–805. PMID 16352683.
5. Nass R, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults. Ann Intern Med. 2008;149(9):601–611. PMID 18981485.
6. Liu H, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med. 2007;146(2):104–115. PMID 17227934.
7. Tomas FM, et al. Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection. J Endocrinol. 1996;150(1):77–84. PMID 8708565.
8. Goldspink G. Mechanical signals, IGF-I gene splicing, and muscle adaptation. Physiology. 2005;20:232–238. PMID 16024511.
9. Staresinic M, et al. Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res. 2006;24(5):1109–1117. PMID 16609979.
10. Novinscak T, et al. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today. 2008;38(8):716–725. PMID 18668315.
11. Chang CH, et al. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol. 2011;110(3):774–780. PMID 21030672.
12. Tokura Y, et al. Muscle injury-induced thymosin β4 acts as a chemoattractant for myoblasts. J Biochem. 2011;149(1):43–48. PMID 20880960.

This article is for educational purposes only and is not medical advice.