Follistatin Protein Enhances Satellite Cell Counts in Reinnervated Muscle

Abstract

Background Muscle recovery following peripheral nerve repair is sup-optimal. Follistatin (FST), a potent muscle stimulant, enhances muscle size and satellite cell counts following reinnervation when administered as recombinant FST DNA via viral vectors. Local administration of recombinant FST protein, if effective, would be more clinically translatable but has yet to be investigated following muscle reinnervation. Objective The aim of this study is to assess the effect of direct delivery of recombinant FST protein on muscle recovery following muscle reinnervation. Materials and Methods In total, 72 Sprague-Dawley rats underwent temporary (3 or 6 months) denervation or sham denervation. After reinnervation, rats received FST protein (isoform FS-288) or sham treatment via a subcutaneous osmotic pump delivery system. Outcome measures included muscle force, muscle histomorphology, and FST protein quantification. Results Follistatin treatment resulted in smaller muscles after 3 months denervation (p = 0.019) and reduced force after 3 months sham denervation (p < 0.001). Conversely, after 6 months of denervation, FST treatment trended toward increased force output (p = 0.066). Follistatin increased satellite cell counts after denervation (p < 0.001) but reduced satellite cell counts after sham denervation (p = 0.037). Conclusion Follistatin had mixed effects on muscle weight and force. Direct FST protein delivery enhanced satellite cell counts following reinnervation. The positive effect on the satellite cell population is intriguing and warrants further investigation.

Control of muscle satellite cell function by specific exercise‐induced cytokines and their applications in muscle maintenance

“…S6 Direct follistatin delivery preserved the SC pool after 6 months following reinnervation. 14 The level of hepatokine selenoprotein P (SeP) seems not to be regulated by exercise in humans in response to acute moderate-intensity exercise, 90 but it increases with type 2 diabetes and aging. 91 Inspiringly, SeP deficiency increased the responsiveness of skeletal muscle in mice and ameliorated muscle atrophy induced by immobilization.…”

“…Follistatin is a well‐known inducer of SC activation, and follistatin overexpression results in a 37% increase in muscle weight in animals by promoting SC proliferation through the inhibition of the expression of myostatin and activin. S6 Direct follistatin delivery preserved the SC pool after 6 months following reinnervation 14 . The level of hepatokine selenoprotein P (SeP) seems not to be regulated by exercise in humans in response to acute moderate‐intensity exercise, 90 but it increases with type 2 diabetes and aging 91 .…”

“…Emerging evidence indicates that the effect of exercise on tissues is largely mediated by circulating molecules induced by exercise, including myokines, hepatokines, osteokines, immune cytokines, and adipokines 10,11 . Several exercise‐induced cytokines, such as irisin, 12 erythropoietin, 13 and follistatin, 14 ,S6 promote the activation of SCs and substantially enhance muscle performance. Some exercise‐induced cytokines, such as Igfbp7 and myostatin, preserve SC quiescence or inhibit SC self‐renewal 15,16 .…”