Since it is not yet clear whether there is a sex-dependent effect on ALS onset and progression in SOD1 mice, nor whether HDAC4 exerts different sex-related functions in ALS muscles, in the present work, we aimed to investigate: (1) ALS outcome in terms of body weight changes, disease onset, and mouse lifespan, comparing the two sexes; and (2) a previously unreported role for HDAC4 function in the skeletal muscle of SOD1 female mice. Here, SOD1 is linked to amyotrophic lateral sclerosis.