What skeletal muscle has to say in ALS: implications for therapy

Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterised by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutations, the origin of most ALS cases remains elusive. Peripheral tissues, and particularly skeletal muscle, have lately demonstrated an active contribution to disease pathology attracting a growing interest for these tissues as therapeutic targets in ALS. In this sense molecular mechanisms essential for cell and tissue homeostasis have been shown to be de‐regulated in the disease. These include muscle metabolism and mitochondrial activity, RNA processing, tissue‐resident stem cell function responsible for muscle regeneration, and proteostasis that regulates muscle mass in adulthood. This review aims to compile scientific evidence that demonstrates the role of skeletal muscle in ALS pathology and serve as reference for development of novel therapeutic strategies targeting this tissue to delay disease onset and progression