Recovery of blood flow regulation in microvascular resistance networks during regeneration of mouse gluteus maximus muscle

Key points

Skeletal muscle regenerates following injury but the recovery of its microvascular supply is poorly understood. We injured the gluteus maximus muscle in mice to study the recovery of blood flow regulation in microvascular resistance networks. We hypothesized that blood flow regulation recovers in concert with myofiber regeneration. Microvascular perfusion ceased within 1d post injury and was restored at 5d coincident with the appearance of new myofibers, however the resistance network was dilated and unresponsive to vasoactive agents. Spontaneous vasomotor tone, endothelium‐dependent dilatation and adrenergic vasoconstriction increased at 10d in concert with myofiber regeneration. Vasomotor control recovered at 21d, when regenerated myofibers matured and active force production stabilized. Functional vasodilatation in response to muscle contraction recovered at 35d. Physiological integrity of microvascular smooth muscle and endothelium recovers in parallel with myofiber regeneration. Additional time is required to restore the efficacy of signaling between myofibers and microvascular networks controlling their oxygen supply.

Abstract

Myofiber regeneration following skeletal muscle injury is well‐studied but little is known of how microvascular perfusion is restored. Our goal was to evaluate the recovery of blood flow regulation during skeletal muscle regeneration. In anesthetized male C57BL/6J mice (age, 4 months), the gluteus maximus muscle (GM) was injured by local injection of barium chloride solution (1.2%, 75 μl). Functional integrity of the resistance network was evaluated at 5, 10, 21 and 35 days post‐injury versus Control by measuring internal diameter of feed arteries (FA), first‐ (1A), second‐ (2A) and third‐order (3A) arterioles supplying the GM using intravital microscopy. Resting diameters of all branch orders were significantly greater (P<0.05) than Control at 5d and 10d and recovered to Control by 21d, as did spontaneous vasomotor tone. Vasodilatation to acetylcholine and vasoconstriction to phenylephrine (10⁻⁹ to 10⁻⁵ M) were absent at 5d, increased at 10d and recovered to Control by 21d; reactivity improved in a distal‐to‐proximal gradient. Across branch orders, functional vasodilatation to single tetanic contraction (100 Hz,500 ms) and to rhythmic twitch contractions (4 Hz,30s) were impaired at 5d, improved through 21d and were not different from Control at 35d. Peak force development (g) was 60% of Control at 10d and recovered by 21d. Diminished vasomotor tone during initial stages of regeneration promotes tissue perfusion as myofiber recovery begins. Recovery of tone and vasomotor responses to agonists occur in concert with myofiber regeneration. Delayed recovery of functional vasodilatation indicates that additional time is required to restore signalling between contracting myofibers and their vascular supply.

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