Satellite Cell Ablation Limits Myofiber Regeneration but Not Angiogenesis Following Skeletal Muscle Injury

Myotoxin injury of skeletal muscle disrupts myofibers and fragments capillaries. Following injury, myofibers and capillaries regenerate in concert; however, it remains unresolved whether myogenesis and angiogenesis are interdependent processes. We tested the hypothesis that myofiber regeneration is required for revascularization. To limit myofiber regeneration, satellite cells were depleted by tamoxifen injections (+TMX) in adult Pax7-CreERT2/+; RosaDTA/+ (Pax7-DTA) mice; vehicle injections (-TMX) served as controls. Two weeks later, the gluteus maximus muscle was injured by local injection of BaCl2. Regeneration of myofibers and microvessels was assessed histologically. Microvascular perfusion was evaluated with fluorescent tracers injected into the bloodstream. Myofiber regeneration was minimal in +TMX. Through 21 days post injury (dpi), microvascular area (CD31 immunostaining) was similar between +TMX and -TMX, with disoriented microvessels prevailing in +TMX. At 7 dpi, fewer capillaries were perfused in +TMX compared to -TMX. At 21 dpi, EC area and capillary perfusion were not different between groups. For +TMX at 28 dpi, distinct regions with fewer perfused microvessels near "ghost" fibers were accompanied by adjacent areas of robust vascularity and clusters of adipocytes. Following myotoxin injury after satellite cell ablation, angiogenesis ensues without myogenesis, and the microcirculation remodels according to changes in tissue composition.