Restoration of neuromuscular function by mitochondrial transplantation in injured mouse skeletal muscle

Rehabilitative activity can improve injury repair, but it risks additional damage and reduces the functional recovery of regenerating muscle. This study tested the hypothesis that moderate electrically evoked contractions would slow restoration of neuromuscular function after cardiotoxin-induced injury; however exogenous mitochondrial transplantation (MT) would enhance recovery of contractile function after injury. Cardiotoxin was injected into the tibialis anterior of C57BL/6 mice (10-12 weeks of age) to induce muscle necrosis. Exogenous mitochondria or phosphate-buffered saline (PBS) were injected into the mouse tail vein after cardiotoxin injury. Injured muscles were either rested or given 40 Hz submaximal electrically evoked contractions to cardiotoxin-injured muscles during the recovery period. Relative to intra-animal non-damaged control muscles restoration of peak tetanic torque after both rested and evoked contractions during recovery and twitch torque was greater, and the difference between control and injured muscle twitch one-half relaxation time was lower in injured muscles that were rested for 10 days after injury and received MT compared to PBS-treated muscles. Neuromuscular junction efficiency in cardiotoxin-injured muscles was ∼70% of control undamaged muscles, but MT improved the recovery of neuromuscular junction efficiency to produce torque by 14 days after cardiotoxin injury in muscles that received additional damage induced by evoked contractions during the recovery period. These data suggest that MT enhances the recovery of neuromuscular function when the muscle is rested after injury, but it provides limited improvement in muscle function when the muscle is challenged with electrically evoked contractions in the recovery period after injury. KEY POINTS: Mitochondrial transplantation by systemically infusing healthy donor mitochondria into injured mice improved the recovery of maximal torque production of injured muscles when evoked contractions were provided to the regenerating muscle during the recovery period after injury. Mitochondrial transplantation improved the restoration of neuromuscular junction efficiency after muscle injury. The recovery of maximal torque capabilities function following cardiotoxin-induced tibialis anterior muscle injury was attenuated by electrically evoked muscle contractions conducted every other day during the recovery period in young adult mice.