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Amyotrophic lateral sclerosis (ALS) progressively impairs motor neurons, leading to muscle weakness and loss of voluntary muscle control. This study compared the effects of SOD1 mutation on masticatory and limb muscles from disease onset to death in ALS model mice. Notably, limb muscles begin to atrophy soon after ALS-like phenotype appear, whereas masticatory muscles maintain their volume and function in later stages. Our analysis showed that, unlike limb muscles, masticatory muscles retain their normal structure and cell makeup throughout most of the disease course. We found an increase in the number of muscle satellite cells (SCs), which are essential for muscle repair, in masticatory muscles. In addition, we observed no reduction in the number of muscle nuclei and no muscle fibre-type switching in masticatory muscles. This indicates that masticatory muscles have a higher resistance to ALS-related damage than limb muscles, likely because of differences in cell composition and repair mechanisms. Understanding why masticatory muscles are less affected by ALS could lead to the development of new treatments. This study highlights the importance of studying different muscle groups in ALS to clarify disease aetiology and mechanisms.

BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities. RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. CONCLUSIONS: The findings from this study suggest that a 6 months treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.