Expanding our understanding of adult-onset myopathy: contributions of satellite cell dysfunction and denervation

Adult-onset genetic myopathies are amongst the most challenging clinical cases to diagnose. These conditions are characterized by extensive genetic heterogeneity, overlapping clinical phenotypes, and poor genotype-phenotype correlation. Symptom onset can occur at any age, and is often confused for acquired disease. As a result, patients often experience a lengthy diagnostic odyssey, in which they can spend years or even decades with diagnostic uncertainty, and without clear guidance regarding the risk to their family members. These conditions are nearly all untreatable due to our lack of knowledge of the underlying disease mechanisms. Genetic myopathies arise from variants in many different proteins. Symptoms begin with selective muscle involvement and gradually progress to include most skeletal muscles, and in some cases, cardiac or respiratory muscles. Prior research has linked some myopathies with differentiation defects and changes at the neuromuscular junction (NMJ). Our work aimed to uncover shared biological disease mechanisms among adult-onset genetic myopathies. We analyzed skeletal muscle biopsies from 10 individuals with genetically confirmed myopathies and 4 unaffected controls. Single nucleus RNA sequencing revealed a group of myonuclei enriched in myopathy that co-express markers of mature muscle and NMJ-associated genes. These nuclei also express key indicators of a denervation response, including RUNX1, CHRNG, NCAM1, and MYOG. Their abundance correlated with the severity of muscle pathology, independent of age or sex. Spatial transcriptomics localized these nuclei to small, angular fibers consistent with denervation and immunostaining showed disrupted patterns of innervation. Analysis of public datasets confirmed elevated expression of NMJ-related genes in other myopathies, notably myotonic dystrophy and polymyositis. These findings suggest that adult myopathic muscle activates a denervation response that may play a role in disease progression. The consistent presence of similar transcriptional signatures across multiple myopathies indicates that denervation may be a common feature of these conditions.