Study of the regenerative capacity of skeletalmuscle stem cells in amyotrophic lateral sclerosis: implications for aperipheral etiopathogenesis

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

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

On the other hand, several mouse modelscarrying mutations in some of the most prevalent ALS causing genes have beencharacterized to elucidate whether these genetic alterations impact overallmuscle homeostasis and regenerative capacity. In hSOD1^G93Amice, an atypical activation and proliferation of SCs was found to occurthroughout disease progression in the tibialis anterior and soleus muscles,possibly reflecting an unsuccessful myogenesis attempt. In fact, the invitro clonogenic capacity of SCs and restoration of the in vivo SCpool upon injury appeared diminished in these mice, suggesting a defect in SCself-renewal. Finally, the specific ablation of TDP-43 in SCs completelyabolished their regenerative capacity upon muscle injury. Transcriptomicanalyses revealed the P53 pathway to be significantly upregulated, upon loss of TDP-43expression.

Together,further characterization of cellular pathways directly regulated by P53 andFOXO may provide clues to preserve the integrity of the skeletal muscle tissuein ALS, facilitating the development of new therapeutic approaches that woulddecelerate disease progression.