Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease 
characterized by loss of both upper and lower motor neurons (MNs). The main 
clinical features of ALS are motor function impairment, progressive muscle 
weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle 
deterioration plays a crucial role in the disease and contributes to ALS 
progression. Currently, there are no effective treatments for ALS, highlighting 
the need to obtain a deeper understanding of the molecular events underlying 
degeneration of both MNs and muscle tissue, with the aim of developing 
successful therapies. Muscle tissue is enriched in a group of microRNAs called 
myomiRs, which are effective regulators of muscle homeostasis, plasticity and 
myogenesis in both physiological and pathological conditions. After providing an 
overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we 
review the current literature on myomiR network dysregulation as a contributing 
factor to myogenic perturbations and muscle atrophy in ALS. We argue that, in 
view of their critical regulatory function at the interface between MNs and 
skeletal muscle fiber, myomiRs are worthy of further investigation as potential 
molecular targets of therapeutic strategies to improve ALS symptoms and 
counteract disease progression.