Advancing β-adrenoreceptor agonism for recovery after volumetric muscle loss through regenerative rehabilitation and biomaterial delivery approaches.

Volumetric muscle loss (VML) injury results in the unrecoverable loss of muscle mass and contractility. Oral delivery of formoterol, a β(2)-adrenergic receptor agonist, produces a modest recovery of muscle mass and contractility in VML-injured mice. The objective of this study was to determine if a regenerative rehabilitation paradigm or a regenerative medicine paradigm could enhance the recovery of VML-injured muscle. Regenerative rehabilitation involved oral formoterol delivery combined with voluntary wheel running. Regenerative medicine involved direct delivery of formoterol to VML-injured muscle using a non-biodegradable poly(ethylene glycol) biomaterial. To determine if the regenerative rehabilitation or regenerative medicine approaches were effective at 8 weeks post-injury, muscle mass, contractile function, metabolic function, and histological evaluations were used. One model of regenerative rehabilitation, in which rehabilitation was delayed until 1 month post-injury, resulted in greater muscle mass, muscle contractility, and permeabilized muscle fiber mitochondrial respiration compared to untreated VML-injured mice. Histologically, these mice had evidence of greater total muscle fiber number and oxidative fibers; however, they also had a greater percentage of densely packed collagen. The regenerative medicine model produced greater permeabilized muscle fiber mitochondrial respiration compared to untreated VML-injured mice; however, the non-biodegradable biomaterial was associated with fewer total muscle fibers and lower muscle quality (i.e. lower muscle mass-normalized contractility). The conclusions reached from this study are: (i) regenerative rehabilitation and regenerative medicine strategies utilizing formoterol require further optimization but showed promising outcomes; and (ii) in general, β-adrenergic receptor agonism continues to be a physiologically supportive intervention to improve muscle contractile and metabolic function after VML injury.