A Potassium Channel Blocker, 4‐Aminopyridine, Attenuates Peripheral Nerve Injury‐induced Muscle Atrophy, Improves Intrinsic Muscle Force, and Suppresses the Expression of Muscle Atrophy‐related Transcription Factors in Mice

Abstract

4‐Aminopyridine (4‐AP), a broad‐spectrum potassium channel blocker and FDA‐approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. The neurological benefits of 4‐AP are believed to result from increases in action potential duration, calcium influx, neurotransmitter release and synaptic transmission. Traumatic peripheral nerve injury (TPNI) represents a major health problem that often leads to significant functional impairment and permanent disability from the loss in axonal continuity, neuronal cell death, nerve demyelination, nerve conduction defects, muscle denervation, and muscle atrophy. We have recently repurposed the use of 4‐AP and demonstrated that systemic 4‐AP administration enhances global functional recovery of the affected limb, promotes remyelination of the nerve and improves the nerve conduction velocity in a mouse model of TPNI. While muscle atrophy occurs very rapidly following nerve injury, the effect 4‐AP on muscle atrophy and muscle contractile function is largely unknown. This study was designed to explore the possible beneficial effects of 4‐AP treatment in muscle atrophy, intrinsic muscle function, and muscle regeneration following acute sciatic nerve crush injury. Mice were assigned to moderate sciatic nerve crush injury and no‐injury groups and followed for 3, 7 and 14 days with/without 4‐AP (10 mg/daily, intraperitoneal injection) or saline treatment. Morphological, functional and transcriptional properties of skeletal muscle were assessed. In addition to improving in vivo global motor function as early as post‐operative day 3, 4‐AP treatment significantly attenuated muscle atrophy of the injured limb with increased muscle mass and muscle fiber area. 4‐AP also improved ex vivo intrinsic muscle contractile force 7 days post‐injury. Most importantly, the reduced muscle atrophy with 4‐AP treatment was concurrent with significantly reduced expression of atrophy‐related genes (myogenin, MuRF‐1, FoxO1, FoxO3) and increased expression of Pax7+ satellite cells and proliferating Ki67+ cells. These findings provide new insights into the beneficial effects of 4‐AP in nerve injury‐induced muscle atrophy and dysfunction and open a new window for further investigation.Support or Funding InformationThis work was supported by grants from the NIH (K08 AR060164‐01A) and DOD (W81XWH‐16‐1‐0725) in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.