Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Age-related reduced regenerative potential and muscle wasting, also called sarcopenia, has been in part associated with a decline in the number and function of muscle stem cells (MuSCs), the direct cellular contributors to muscle repair. Despite the clinical and social impact of sarcopenia, the age-related decline of muscle mass and function is not entirely deciphered. In our lab it has been recently demonstrated the essential role of autophagy in regulating MuSCs function and the role of STAT3 in regulating MuSCs expansion and myogenic differentiation extending its use as therapeutic target to ameliorate muscle wasting. Emerging evidences underline the importance of STAT3 signaling in modulating the autophagic process inspiring the rationale beside this project. The final outcome will be to investigate on the contribution of STAT3-mediated autophagy toward skeletal muscle repair hence counteracting muscle degeneration that occurs during aging.
This project is innovative because it is based on the study of Lucia Latella and Alessandra Sacco's lab showing that transient STAT3 inhibition promotes muscle regeneration in vivo (Tierney et al. 2016), demonstrating that this molecule could be a relevant target to be tested for the development of therapeutic approaches for muscle wasting. Moreover, Lucia Latella's lab has demonstrated that autophagy is essential in improving muscle regeneration (Fiacco et al.,2016). The importance of this proposal lies on increasing our knowledge on the molecular mechanisms regulating MuSCs activation upon tissue injury, focusing in particular on the STAT3-dependent function that regulates autophagy to support muscle regeneration. The main goal of this proposal will be to investigate the biological relationship between STAT3, autophagy and reduced muscle regeneration that occur in aging and to develop combinatorial therapies as such pharmacological STAT3i treatment and boosting the autophagic process (for example by Calorie Restriction) to improve MuSCs mediated tissue regeneration and to counteract the functional decline of muscle-wasting diseases.