Muscle contractility dysfunction precedes loss of motor unit connectivity in SOD1(G93A) mice

Abstract

Introduction: Electrophysiological measurements are used in longitudinal clinical studies to provide insight into the progression of amyotrophic lateral sclerosis (ALS) and the relationship between muscle weakness and motor unit (MU) degeneration. Here, we used a similar longitudinal approach in the Cu/Zn superoxide dismutase (SOD1[G93A]) mouse model of ALS. Methods: In vivo muscle contractility and MU connectivity assays were assessed longitudinally in SOD1(G93A) and wild type mice from postnatal days 35 to 119. Results: In SOD1(G93A) males, muscle contractility was reduced by day 35 and preceded MU loss. Muscle contractility and motor unit reduction were delayed in SOD1(G93A) females compared with males, but, just as with males, muscle contractility reduction preceded MU loss. Discussion: The longitudinal contractility and connectivity paradigm employed here provides additional insight into the SOD1(G93A) mouse model and suggests that loss of muscle contractility is an early finding that may precede loss of MUs and motor neuron death.

The final frontier: Primary muscle dysfunction in amyotrophic lateral sclerosis

“…Moreover, minor alterations in motor neuron or neuromuscular junction health or activity could produce subtle secondary disuse changes in the muscle with an associated reduction in contractility. Indeed, mean triceps surae mass in ALS animals was slightly lower than that of the wild‐type animals, although this was not significant in this study. Finally, the limitations of the mouse model of ALS are well known.…”

“…The study by Wier et al . in this issue of Muscle & Nerve has attempted to do just that by using the well‐studied superdioxide dismutase 1 (SOD1) G93A mouse model of the disease.…”

Assessing Rat Forelimb and Hindlimb Motor Unit Connectivity as Objective and Robust Biomarkers of Spinal Motor Neuron Function

“…Despite the myriad advantages of an objective electrophysiological measure of motor unit loss, the limited application of MUNE in pre-clinical rodent studies has been restricted to the hindlimb 22,26,42,43 . The goal of this study was to develop and validate forelimb electrophysiological measures of motor unit connectivity as biomarkers of spinal motor neuron degeneration/dysfunction in the rat.…”

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…Patients with ALS develop weakness, muscle denervation, atrophy and progressive paralysis of all muscles (bulbar and respiratory), dysphagia (Al-Chalabi and Hardiman, 2013;D'Amico et al, 2013;Gowland et al, 2019) and respiratory muscle weakness that leads to respiratory failure and death (Sferrazza-Papa et al, 2018). The survival rate is 3-5 years after the onset of symptoms (Andersen, 2006;Gordon, 2013;Coan and Mitchell, 2015;Wier et al, 2019).…”

“…Neurodegenerative diseases are associated with a progressive decrease in muscle mass and strength and an increase in their weakness (González et al, 2017;Van Damme et al, 2017;Dahlqvist et al, 2019). Muscle contractility dysfunction precedes the loss of motor unit connectivity in the SOD1 G93A mouse model of ALS (Wier et al, 2019) with neurodegeneration being one of the determinant risk factors for muscle quality (Di Pietro et al, 2017;Moon et al, 2018). Treatment with NR improves muscle function in aged mice (Cantó et al, 2012) and has benefits on muscle strength and skeletal muscle resistance in knock out mice that have specific elimination of NAMPT and a decrease of 85% in the intramuscular content of NAD + (Frederick et al, 2016).…”