Study of the regenerative capacity of skeletal muscle stem cells in amyotrophic lateral sclerosis: implications for a peripheral etiopathogenesis

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset disease characterized by gradual degeneration of upper and lower motor neurons (MN) which leads to progressive muscle weakness and paralysis. Non-cell autonomous mechanisms are nowadays considered to play a crucial role in its onset and progression. Thus, the skeletal muscle is hypothesized to actively contribute to ALS pathogenesis.

Firstly, histopathological analyses on ALS patient-derived muscle tissue have revealed a significant proportion of satellite cells (SC), the bona fide muscle stem cells, to be activated. These however cannot progress in myogenesis, and, therefore, perform their regenerative function. In line with this, myogenic alterations were identified in ALS muscle progenitors in vitro, related to the loss-of-function of TDP-43 and FOXO1 dysregulation.

On the other hand, several mouse models carrying mutations in some of the most prevalent ALS causing genes have been characterized to elucidate whether these genetic alterations impact overall muscle homeostasis and regenerative capacity. In hSOD1^G93A mice, an atypical activation and proliferation of SCs was found to occur throughout disease progression in the tibialis anterior and soleus muscles, possibly reflecting an unsuccessful myogenesis attempt. In fact, the in vitro clonogenic capacity of SCs and restoration of the in vivo SC pool upon injury appeared diminished in these mice, suggesting a defect in SC self-renewal. Finally, the specific ablation of TDP-43 in SCs completely abolished their regenerative capacity upon muscle injury. Transcriptomic analyses revealed the P53 pathway to be significantly upregulated, upon loss of TDP-43 expression.

Together, further characterization of cellular pathways directly regulated by P53 and FOXO may provide clues to preserve the integrity of the skeletal muscle tissue in ALS, facilitating the development of new therapeutic approaches that would decelerate disease progression.