Identifying a New Mechanism of Sarcopenia by Autophagy

Sarcopenia is one of the critical factors in reducing Activity of Daily Life and associated with morbidity and mortality. Sarcopenia has also been linked to metabolic syndrome. In recent years, it has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. Therefore, we focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation, mainly using transgenic mice (Cell metabolism 2010, Cell Rep. 2012). However, since these were non-physiological studies, we proceeded with further studies and demonstrating that Fyn dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6 dependent and Fyn dependent mechanisms. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions as well as the key muscle specific E3 ubiquitin ligases, Atrogin1 and MuRf1 were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not enough as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle with Atrogin1 and MuRf1 increased. Increase of both IL6 and STAT3 expression/phosphorylation were also observed in the muscles of hind limb suspension mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods.