Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that 
leads to progressive degeneration of motor neurons (MNs) and severe muscle 
atrophy without effective treatment. Most research on ALS has been focused on 
the study of MNs and supporting cells of the central nervous system. Strikingly, 
the recent observations of pathological changes in muscle occurring before 
disease onset and independent from MN degeneration have bolstered the interest 
for the study of muscle tissue as a potential target for delivery of therapies 
for ALS. Skeletal muscle has just been described as a tissue with an important 
secretory function that is toxic to MNs in the context of ALS. Moreover, a 
fine-tuning balance between biosynthetic and atrophic pathways is necessary to 
induce myogenesis for muscle tissue repair. Compromising this response due to 
primary metabolic abnormalities in the muscle could trigger defective muscle 
regeneration and neuromuscular junction restoration, with deleterious 
consequences for MNs and thereby hastening the development of ALS. However, it 
remains puzzling how backward signaling from the muscle could impinge on MN 
death. This review provides a comprehensive analysis on the current 
state-of-the-art of the role of the skeletal muscle in ALS, highlighting its 
contribution to the neurodegeneration in ALS through backward-signaling 
processes as a newly uncovered mechanism for a peripheral etiopathogenesis of 
the disease.