The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…Masitinib treatment also prevented the regressive remodeling of perisynaptic Schwann cells described in ALS (67,68). Because Schwann cell dissociation from NMJ is mainly caused by the axon retraction from motor plates (17,68), our results further suggest the halt of distal motor axon degeneration following treatment with masitinib.…”

Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis

“…In the present study, edaravone treatment significantly reduced the oxidative stress serum markers dROM and the OS index, and Nrf2 expression in spinal motor neurons and LL myofibers (Figures d,e, , , ). It also reduced the expressions of PGC1α and HDAC4 in myofibers (Figure ), suggesting edaravone treatment enhanced mitochondrial function and muscle development (Loeffler et al, ; Petri et al, ; Thau et al, ). Furthermore, edaravone treatment ameliorated neurogenic myofiber atrophy, spinal motor neuron loss, astrogliosis and motor performance impairment measured by the rotarod test in Nrf2/G93A mice (Figures c, , ).…”

“…ALS skeletal muscles are involved in oxidative stress, mitochondrial dysfunction and bioenergetic disturbances (Loeffler et al, ; Tsitkanou et al, ). In the present study, Nrf2/G93A mice showed neurogenic myofiber atrophy, denervated NMJ and Nrf2 expression of small quadriceps myofibers in LL, which were significantly alleviated by edaravone, except for the NMJ denervation (Figures ).…”

“…We previously reported the Nrf2 activation in spinal motor neurons of ALS model mice bearing G93A‐SOD1 (Mimoto et al, ), and another report showed a higher ARE activation in skeletal muscles than the spinal cords of the same model mice (Kraft, Resch, Johnson, & Johnson, ). ALS skeletal muscles are involved in several pathogeneses, including oxidative stress (Loeffler, Picchiarelli, Dupuis, & Gonzalez De Aguilar, ; Tsitkanou, Della Gatta, & Russell, ), but previous reports rarely focused on the contribution of ALS muscles to the pathological process.…”

Further development of biomarkers in amyotrophic lateral sclerosis

“…One limit is the availability of CSF and the consequent challenge of finding adequate controls. The main advantage of blood samples is the ability of collection during longitudinal studies; thus, it is Some studies have advocated that muscle per se may be impaired by the pathogenesis of the disease, principally through the "dying-back" phenomenon [17] [18]. Muscle has been poorly studied, and its central role in energetic metabolism suggests that this tissue warrants further analysis in order to find biomarkers and to compare muscular metabolism with those of the brain and the body overall [19].…”