Pedersen, T. H. | bioRxiv Science

bioRxiv2026

The muscle atrophic phenotype of MuSK myasthenia gravis: Insights from a preclinical rat model

Myasthenia gravis with muscle-specific kinase antibodies (MuSK-MG) is an autoimmune disorder marked by neuromuscular junction (NMJ) disruption and selective muscle atrophy, yet its intrinsic myocellular mechanisms remain unclear. Using a rat model generated by active immunization with the N-terminal MuSK60 peptide, we characterized muscle pathology, NMJ morphology, and whole-muscle proteome remodeling across anatomically distinct skeletal muscles. Anti-MuSK rats developed seropositivity, body-mass loss, fragmented and denervated NMJs, and pronounced atrophy restricted to slow-twitch/type I fibers, particularly in the soleus muscle. Quantitative proteomics identified extensive muscle-specific alterations, most prominent in soleus, with fewer in diaphragm and sternohyoideus. Gene set enrichment analysis revealed coordinated downregulation of mitochondrial, ribosomal, and myosin-complex proteins in soleus, partial mitochondrial involvement in diaphragm, and compensatory upregulation of translational and proteasomal pathways in diaphragm. Correlation analysis linked soleus mass loss to elevated abundance of ubiquitin-proteasome and calcium-handling proteins, implicating proteolytic and bioenergetic stress mechanisms. The consistent upregulation of NCAM1 and MUSTN1 suggests generalized myocellular responses to MuSK dysfunction. Together, these data demonstrate that MuSK autoimmunity elicits fiber-type-selective atrophy and profound proteome remodeling beyond NMJ impairment, highlighting disrupted mitochondrial and translational homeostasis as central features of the MuSK-MG muscle phenotype.

molecular biology↗

bioRxiv2025

Chill tolerant Drosophila species maintain electrogenic muscle membrane potential to resist cold-induced depolarization

The ability to tolerate low temperature is among the most important traits defining the functional niche of insects and it clear that cold tolerance of most insects is intimately linked to their ability to defend membrane potential (Vm). Failure to maintain membrane polarization results in loss of neuromuscular function and may ultimately initiate cell death and organismal injury. Prolonged cold exposure challenges membrane polarization through loss of transmembrane ion balance; however, the insect muscle Vm is also dependent on a strong and temperature-dependent electrogenic effect driven by Na+/K+-ATPase activity. In the present study we investigate the electrogenic contribution of the Na+/K+-ATPase at benign (20{degrees}C) and low (0{degrees}C) temperature in ten Drosophila species representing a broad spectrum of chill tolerance. We find that the electrogenic effect of the Na+/K+-ATPase contributes a considerable component of the muscle Vm in all ten species at 20{degrees}C. This electrogenic contribution is reduced significantly at 0{degrees}C in the chill sensitive species, while tolerant species retain their electrogenic effect at low temperature. Thus, the initial cold-induced muscle depolarization, that is a hallmark of chill sensitive insects, is largely caused by loss of Na+/K+-ATPase-dependent electrogenic polarization. We hypothesized that maintenance of Na+/K+-ATPase activity in the cold would be energetically costly, but in contrast to our hypothesis we find no evidence for major energetic costs in the species that maintain membrane polarization at low temperature. On the basis of these observations we discuss how other adaptations at the protein or membrane level could explain the observed intraspecific differences.

physiology↗