Polyamine metabolism dysregulation in ALS- and aging-related muscle wasting

Skeletal muscle wasting is a hallmark of both Amyotrophic Lateral Sclerosis (ALS) and aging, yet the molecular determinants of fiber-type specific vulnerability remain poorly understood. Fast-twitch glycolytic fibers are consistently more susceptible to atrophy across species, including humans, whereas slow oxidative fibers are relatively spared. This selective vulnerability is well illustrated in murine models where fast-twitch muscles, such as the tibialis anterior (TA), undergo early and pronounced atrophy, while slow-twitch muscles, such as the soleus, are affected only at later stages. This thesis identifies polyamine metabolism as a central regulator of muscle vulnerability, with the key enzymes Amd1 and Smox selectively downregulated in the most affected, atrophic muscles of mouse models across multiple contexts, including ALS, traumatic denervation and aging. In these vulnerable muscles, polyamine flux is altered and correlates with fiber atrophy, while resistant muscles, such as the soleus, maintain unaltered enzymes expression and polyamine levels. In ALS-affected muscles, Amd1 and Smox downregulation occurs alongside Odc1 upregulation, leading to the accumulation of putrescine and spermidine, whereas during aging, this downregulation occurs without Odc1 induction, resulting mainly in spermidine deficiency. Functional experiments further support a casual role for polyamine dysregulation in muscle vulnerability. Specifically, inhibiting Amd1 reduces myotube diameter in vitro and fiber cross-sectional area in vivo. Moreover, polyamine perturbation extends beyond muscle fibers to the muscle niche. Inhibition of Amd1 in fibro-adipogenic progenitors (FAPs) induces an aging-like phenotype and impairs their ability to support satellite cell-mediated myogenesis. Finally, therapeutic modulation of polyamine metabolism in ALS mice ameliorates muscle pathology, reducing atrophy and increasing mass in the most vulnerable muscles. In summary, this study identifies polyamine dysregulation as a shared signature of muscle atrophy and a tractable target for therapeutic intervention, offering new perspectives for preserving muscle health in ALS and aging.