UC San Diego

Skeletal muscle relies mostly on its resident progenitor cells, the satellite cells, for postnatal growth and regeneration. Therefore, maintaining proper function and healthy population of satellite cells are critical for the ability of muscle to control damage. Endurance exercise elicits a myriad of adaptive responses in the muscle, including an increase in the satellite cell number. Targeted expression of constitutively active Peroxisome Proliferator-Activated Receptor delta (VP16-PPAR[delta]) in the skeletal muscle mimics endurance training induced fiber type remodeling, including, glycolytic to oxidative fiber type switch and concomitant increase in the running capacity. Currently, however, it is unknown whether transcriptionally directed "endurance exercise training" adaptations by PPAR[delta] in the muscle is sufficient to affect satellite cell homeostasis and function. We herein present that PPAR[delta] activation promotes acceleration of regenerative process after an acute injury. We found that the skeletal muscle specific over-expression of PPAR[delta] induces increase in the satellite cell population. Furthermore, we observed an increase in the number of proliferating cells after injury, leading to an increase in the number of nascent regenerating fibers. Gene expression analyses showed an earlier resolution of inflammatory response and induction of myogenic markers, suggesting that PPAR[delta] actuates temporal shift of the regenerative process. Interestingly, PPAR[delta] promotes myoblast proliferation immediately after the injury, which correlates with strong induction of Notch signaling pathway by PPAR[delta]. Additionally, acute pharmacological activation of PPAR[delta] also promoted efficient restoration of fiber integrity. Collectively, our results demonstrate a new role for PPAR[delta] in skeletal muscle regeneration. Our findings allude to the therapeutic potential of PPAR[delta], not only for the treatment of an acute injury, but also in Notch-dependent aging associated loss of regenerative capacity of the muscle