American Society for Peripheral Nerve

Back to 2020 ePosters

4-Aminopyridine Attenuates Neurogenic Muscle Atrophy After Sciatic Nerve Crush Injury in Mice
John C Elfar, MD, FACS1, Li Yue, PhD2, Anagha Gurjar, PhD1, Jungil Lee, MD PhD3 and M A Hassan Talukder, MBBS, PhD4, (1)The Pennsylvania State University, Hershey, PA, (2)Universtiy of Rochester, Rochester, NY, (3)Hanyang University Guri Hospital, Seoul, Korea, Republic of (South), (4)The Pennsylvania State University College of Medicine, Hershey, PA

Introduction:4-Aminopyridine (4-AP), a 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, synaptic transmission, and direct effect on the muscle. 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, conduction defects, and muscle denervation. While innervation of skeletal muscle is essential for the maintenance of muscle size, structure, and contractile function, denervation results in contractile deficits and rapid muscle-fiber atrophy within the first two weeks. Muscle atrophy is associated with increased atrophy genes (atrogenes) including Muscle Ring Finger 1(MuRF-1) and Muscle Atrophy F-box (MAFbx or atrogin-1) and specific signaling pathways. Importantly, myogenin is upregulated early in skeletal muscle following denervation and promotes the expression of MuRF-1 and atrogin-1. 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.

Materials & Methods: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, intra-peritoneal injection) or saline treatment. Morphological, functional and transcriptional properties of skeletal muscle were assessed.

Results:In addition to improving in vivoglobal 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 vivointrinsic 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 cellsand proliferating Ki67+ cells.

Conclusions: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.

Back to 2020 ePosters