PGC-1α modulates skeletal muscle regeneration by affecting immune response and satellite cell behavior

The benefits of exercise on wellbeing have been known to mankind for thousands of years, yet the underlying mechanisms of exercise have been explained only relatively recently. Today we know that lack of exercise is associated with many chronic pathologies, and that regular moderate exercise, on the other hand, can improve human health. Signaling pathways activated by endurance exercise lead to skeletal muscle adaptations, and at the core of these adaptations lies peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). These modulations brought about by PGC-1α enhance muscle endurance, and protect against several atrophic conditions. In addition, endurance exercise has been shown to increase the number of satellite cells and regenerative potential of skeletal muscle. However, in some pathologies, exercise is not an option for improvement of systemic and muscle phenotype. Interestingly, experiments in mice have revealed that overexpressing PGC-1α mimics the effects of exercise, and that this is associated with a fiber type switch towards a more oxidative phenotype. Although PGC-1α was shown to palliate dystrophic condition by protecting muscles from damaging effects of contractions, PGC-1α’s effects on satellite cells and regeneration have not been investigated. In addition, the causes of the protective role of PGC-1α in muscle have not been elucidated. Using mouse models with overexpression and deletion of PGC-1α specifically in skeletal muscle, in combination with cardiotoxin injury, we have investigated the contribution of PGC-1α to skeletal muscle regeneration. Our results indicate that PGC-1α improves muscle’s initial response to injury resulting in a faster removal of necrotic tissue. Additionally, PGC-1α reduces fibrosis development in a model of chronic damage. Considering the PGC-1α levels in regenerating muscles, these differences were probably driven by the preexisting milieu of muscle residing inflammatory cells dependent on PGC-1α expression in myofibers, and were associated with myostatin and insulin-like growth factor 1 (IGF-1) levels prior and after injury, respectively. However, overall regeneration was neither impaired nor improved with PGC-1α deletion or overexpression. We detected a reduction in satellite cell numbers in PGC-1α overexpressing mice. This was surprising, given that oxidative fibers contain more satellite cell. Ex vivo experiments further revealed that PGC-1α levels also influence satellite cell response to activating stimuli, and that increased PGC-1α in the fiber (satellite cell niche) results in faster activation and proliferation of these cells. The effect on satellite cell behavior was at least partially due to reduced fibronectin levels in the basal lamina of transgenic mice. Deletion of PGC-1α from satellite cells and their niche resulted in the opposite phenotype. We also sought to explore the mechanism through which PGC-1α increases protection in dystrophic skeletal muscle. In transgenic mice, we detected increased synaptotagmin VII, the deletion of which results in myopathy. On the other hand, knocking-down PGC-1α in C2C12 myoblasts reduced the resealing capacity of the sarcolemma. In addition, an increase in integrin 7α observed after exercise was absent in PGC-1α knock-out mice. These results suggest increased sarcolemma stability and propensity for repair dependent on PGC-1α levels in muscles. Finally, in a proof-of-principal study addressing applications in regenerative medicine, we wanted to explore whether adenoviral delivery and induction of PGC-1α in human myoblasts can improve skeletal muscle formation after myoblast transplantation. Apart from the foreseen benefits based on previously published research, we can speculate that PGC-1α might surpass our expectations and significantly improve not just the survival and function of newly-formed tissue, but also, based on the data presented here, improve the regenerative capabilities of skeletal muscle. The results reported here could potentially expand the therapeutic benefits of PGC-1α induction in skeletal muscle myopathies. However, further research is necessary in order to fully understand these effects before using PGC-1α to facilitate skeletal muscle repair and regeneration, especially having in mind the discrepancies in PGC-1α induction and oxidative fiber phenotypes in relation to satellite cell numbers.