Integrated analysis of skeletal muscle from Vps13a-/- mice showed neuro-myopathic metabolic signature and impaired autophagy

Chorea acanthocytosis (ChAc) is an ultra-rare, highly invalidating disease due to mutations on VPS13A gene. ChAc is characterized by progressive movement disorder including chorea, behavior and cognitive disorders, dystonia, parkinsonism, myopathy and acanthocytosis. One of the early clinical manifestations of ChAc is the increased serum creatine kinase (CK) of muscular origin generally associated with progressive muscular weakness. Here, we analyzed skeletal muscles from mice genetically lacking Vps13a (Vps13a-/-) a mouse model of ChAc. Metabolomic analysis revealed oxidation and abnormalities in tryptophan and catecholamine pathways with accumulation of serotonin, suggesting a perturbation of protein trafficking in neuromuscular junction associated with oxidation. Since autophagy plays an important role in proteostasis, we evaluated key proteins of autophagy in muscles from Vps13a-/- mice. These studies revealed an impairment of autophagy in muscles from Vps13a-/- mice. This induces endoplasmic reticulum stress, resulting in activation of the Unfolded Protein Response system in Vps13a-/- mice muscles. The pro-oxidant environment characterizing muscles from Vps13a-/- mice promotes the activation of NF-kB and Nrf2, two important transcriptional factors involved in cell response against oxidation and inflammation. Indeed, we observed local up-regulation of cytokines such as Il1b and TNFα as well as Nrf2-related antioxidant systems. Finally, we took advantage of the availability of muscles’ biopsy from patients with ChAc. In human samples, we found accumulation of autophagy related proteins in presence of increased LC3II, similarly to that observed in Vps13a-/- mice. This was associated again with increased protein oxidation and activation of NF-kB transcriptional factor, paralleling the findings in the murine model for ChAc. In conclusion, our data identify a metabolic perturbation of muscles from Vps13a-/- mice, involving neuro-muscular junction homeostasis most likely due to abnormalities in protein trafficking. Indeed, we found impaired autophagy associated with accumulation of poly-ubiquitinated proteins and 4 ER stress. Further studies are required to better define the mechanism linking Chorein to neuro-muscular junction in ChAc.