Follistatin gene therapy is an effective means of addressing two of the most significant health crises today: age-related frailty due to sarcopenia (muscle loss over time) and Metabolic Syndrome – a constellation of issues including insulin insensitivity, hypertension, high cholesterol, and excess body fat (Cornier, 2008). Heart disease is the leading cause of death in the developed world; aging and Metabolic Syndrome are its primary contributors.
Follistatin gene therapy has been used with success in patients with Duchenne and Becker’s muscular dystrophy safely and effectively (Mendel 2012; Mendel, 2015). In healthy subjects given epicatechin (a compound that elevates follistatin levels) markedly increased their grip strength, which though seemingly crude, is a good biomarker of general health and predictor of all-cause mortality. They saw this happen within one week (Guieterez et. al, 2014) .
Follistatin is a myostatin inhibitor, although this is certainly not where its benefits end. Myostatin is a protein that limits muscle growth. Blocking myostatin allows muscles to grow freely. The images of “double-muscled” animals circulating around the internet are the products of myostatin mutations. They are not (all of them, anyway) the products of a Photoshop artist’s fevered imagination.
However, the responsible use of myostatin inhibitors do not produce these grotesque results. They are of interest to organizations like Integrated Health Systems because of the tremendous potential they have to help the elderly. Though regular exercise and sensible diets can curb muscle loss, the process is inexorable. That’s why after a certain age follistatin gene therapy may become as routine as a yearly checkup. The cosmetic benefits of increased muscle mass and decreased body fat are obvious, but the benefits to health and well-being are immeasurably greater.
While myostatin inhibition may be the main way follistatin enhances muscle growth, it is not the only one. In mice engineered to have no myostatin, follistatin still improved muscle growth in the experimental group (Lee, 2007). The loss of skeletal muscle over time leads to frailty and reduced mobility. That is easy to see. It also sets into motion a series of insidious changes that culminate in Metabolic Syndrome.
Insulin insensitivity and atherosclerotic plaques are nasty topics most of us would rather avoid. However, like so many unpleasant things, they have a habit of eventually, unless we are unusually lucky (or unlucky enough to die suddenly in an unforeseen calamity), find us. As a gene therapy, something that can require only one or two injections in a lifetime, follistatin is a long-term solution to issues that can quietly build for decades before striking in the form of a stroke or heart attack.
The loss of intramuscular fat, mentioned at the beginning of this article, is associated with an assortment of beneficial metabolic changes (as well as leaner musculature). However, everyone, including those with significant genetic disadvantages and those who cannot engage in strenuous exercise, can benefit. That is the beauty of myostatin inhibiting gene therapy.
Optimal body composition is important for maintaining healthy cholesterol levels and preventing hypertension (Butcher, 2018). High cholesterol is one of the contributors to atherosclerosis, the accumulation of arterial plaque. Lower levels of muscle mass have been repeatedly linked to an increased risk of atherosclerosis (Ko, 2016; Ochi 2010). Some may point to the fact that diet and exercise may be confounding factors. However, it appears that total muscle mass, in and of itself, is protective – its previously mentioned benefits to metabolic health are the likely cause.
Ochi’s group concluded that “low relative muscle mass was associated with an increased prevalence of subclinical coronary artery disease and the degree of CAC in a dose-dependent manner. This association remained significant after adjustment for many possible confounders, including HOMA-IR, and was consistently observed in various subgroups.”
Myostatin inhibition can be an amazing thing, but like Klotho and telomerase, follistatin is versatile. Ostopenia, the loss of bone density over time, is also a key player in age-related frailty. By blocking GDF-11, follistatin fights bone loss while simultaneously fighting the loss of muscle mass over time through a pathway independent of myostatin (Egerman, 2011).
26 subjects with male pattern baldness showed significant improvement from a single injection of follistatin and other growth factors (Zierling, 2011). The total number of hairs on their head as well as follicle and hair shaft thickness increased after treatment.
Butcher, Joshua T., et al. “Increased muscle mass protects against hypertension and renal injury in obesity.” Journal of the American Heart Association 7.16 (2018): e009358.
Cornier, Marc-Andre, et al. “The metabolic syndrome.” Endocrine reviews 29.7 (2008): 777-822.
Egerman, Marc A., et al. “GDF11 increases with age and inhibits skeletal muscle regeneration.” Cell metabolism 22.1 (2015): 164-174.
Gutierrez-Salmean, Gabriela, et al. “Effects of (−)-epicatechin on molecular modulators of skeletal muscle growth and differentiation.” The Journal of nutritional biochemistry 25.1 (2014): 91-94.
Lee, Se-Jin. “Quadrupling muscle mass in mice by targeting TGF-ß signaling pathways.” PloS one 2.8 (2007): e789.
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Mendell, Jerry R., et al. “Gene therapy for muscular dystrophy: lessons learned and path forward.” Neuroscience letters 527.2 (2012): 90-99.
Ko, Byung-Joon, et al. “Relationship between low relative muscle mass and coronary artery calcification in healthy adults.” Arteriosclerosis, thrombosis, and vascular biology 36.5 (2016): 1016-1021.
Ochi, Masayuki, et al. “Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men.” Atherosclerosis 212.1 (2010): 327-332.
Riley, Lance A., and Karyn A. Esser. “The role of the molecular clock in skeletal muscle and what it is teaching us about muscle-bone crosstalk.” Current osteoporosis reports 15.3 (2017): 222-230.
Smith, Rosamund C., and Boris K. Lin. “Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders.” Current opinion in supportive and palliative care 7.4 (2013): 352.
Ziering, Craig, et al. “Hair Regrowth Following a Wnt-and Follistatin-Containing Treatment: Safety and Efficacy in.” J Drugs Dermatol 10.11 (2011): 1308-1312.