Deficient Sarcolemma Repair in ALS: A Novel Mechanism with Therapeutic Potential

The plasma membrane (sarcolemma) of skeletal muscle myofibers is susceptible to injury caused by physical and chemical stresses during normal daily movement and/or under disease conditions. These acute plasma membrane disruptions are normally compensated by an intrinsic membrane resealing process involving interactions of multiple intracellular proteins including dysferlin, annexin, caveolin, and Mitsugumin 53 (MG53)/TRIM72. There is new evidence for compromised muscle sarcolemma repair mechanisms in Amyotrophic Lateral Sclerosis (ALS). Mitochondrial dysfunction in proximity to neuromuscular junctions (NMJs) increases oxidative stress, triggering MG53 aggregation and loss of its function. Compromised membrane repair further worsens sarcolemma fragility and amplifies oxidative stress in a vicious cycle. This article is to review existing literature supporting the concept that ALS is a disease of oxidative-stress induced disruption of muscle membrane repair that compromise the integrity of the NMJs and hence augmenting muscle membrane repair mechanisms could represent a viable therapeutic strategy for ALS.

Automated summary

The sarcolemma of skeletal muscle myofibers is susceptible to injury, and the repair mechanisms are compromised in ALS. Mitochondrial dysfunction near neuromuscular junctions leads to oxidative stress and worsens the fragility of sarcolemma. Enhancing membrane repair mechanisms could be a viable therapeutic strategy for ALS.