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

Introduction

Skeletal muscle oxidative capacity decreases and fatigability increases after spinal cord injury. Transcription factor peroxisome proliferator-activated receptor δ (PPARδ) promotes a more oxidative phenotype.

Methods

We asked whether PPARδ overexpression could ameliorate these deficits in the medial gastrocnemius of spinal cord transected (ST) adult mice.

Results

Time-to-peak tension and half-relaxation times were longer in PPARδ-Con and PPARδ-ST compared with littermate wild-type (WT) controls. Fatigue index was 50% higher in PPARδ-Con than WT-Con and 70% higher in the PPARδ-ST than WT-ST. There was an overall higher percent of darkly stained fibers for succinate dehydrogenase in both PPARδ groups.

Conclusions

The results indicate a conversion toward slower, more oxidative, and less fatigable muscle properties with overexpression of PPARδ. Importantly, the elevated fatigue resistance was maintained after ST, suggesting that enhanced PPARδ expression, and possibly small molecule agonists, could ameliorate the increased fatigability routinely observed in chronically paralyzed muscles.