Myofiber injury induces capillary disruption and regeneration of disorganized microvascular networks

Abstract

Myofibers regenerate following injury, however the microvasculature must also recover to restore skeletal muscle function. We aimed to define the nature of microvascular damage and repair during skeletal muscle injury and regeneration induced by BaCl2. To test the hypothesis that microvascular disruption occurred secondary to myofiber injury in mice, isolated microvessels were exposed to BaCl2 or the myotoxin was injected into the gluteus maximus (GM) muscle. In isolated microvessels, BaCl2 depolarized smooth muscle cells and endothelial cells while increasing [Ca2+]i, but did not elicit cell death. At 1 day post injury (dpi) of the GM, capillary fragmentation coincided with myofiber degeneration while arteriolar and venular networks remained intact; neutrophil depletion before injury did not prevent capillary damage. Perfused capillary networks reformed by 5 dpi in association with more terminal arterioles and were dilated through 10 dpi; with no change in microvascular area or branch point number in regenerating networks, fewer capillaries aligned with myofibers and capillary networks were no longer organized into microvascular units. By 21 dpi, capillary orientation and organization had nearly recovered to that in uninjured GM. We conclude that following their disruption secondary to myofiber damage, capillaries regenerate as disorganized networks that remodel while regenerated myofibers mature.