C-peptide promotes myogenic differentiation in vitro and low serum levels are associated with sarcopenia in adults and the elderly

Background: Sarcopenia, the age-related loss of muscle mass and function, is a growing public health problem. Its multifactorial causes including poor nutrition, physical inactivity, and underlying diseases. Research suggests a role for C-peptide in muscle regulation, but its link to sarcopenia is unclear. We hypothesized that low C-peptide associates with sarcopenia and fractures, and that it promotes myogenesis and protects muscle cells from atrophic damage in vitro. Methods: In this cross-sectional study, we analysed data from 191 individuals aged 50 or older, including serum C- peptide and appendicular skeletal muscle mass measurements, along with falls and fractures assessed at follow-up. Skeletal muscle parameters were evaluated using bioelectrical impedance analysis. In parallel, in vitro experiments were performed in C2C12 cells to investigate the effects of C-peptide on myogenic differentiation and its protective role against muscle damage. Results: Individuals in the lowest C-peptide tertile had significantly less appendicular skeletal muscle/sarcopenia than those in the highest (p<0.001). Lower C-peptide significantly increased sarcopenia odds (OR: 0.34; p<0.001). These individuals also showed higher falls (32%) and fractures (17%) rates compared to the highest tertile (14% and 0%). Fractures were linked to falls and low C-peptide levels (OR: 0.29; p=0.01). In vitro, C-peptide promotes myogenic differentiation and reduced muscle damage in C2C12 myotubes. Conclusions: Our findings suggest the protective role of C-peptide in musculoskeletal health, demonstrating that higher levels are associated with a reduced risk of having low appendicular skeletal muscle mass/sarcopenia and fractures in adults and the elderly. Moreover, C-peptide enhances myogenic differentiation and protects against in vitro nutrient-deprivation muscle damage. Further studies are warranted to explore the therapeutic utility of C- peptide for the prevention of sarcopenia and fractures in adulthood and aging.