DOCK (dedicator of cytokinesis) is an 11-member family of typical guanine nucleotide exchange factors (GEFs) expressed in the brain, spinal cord, and skeletal muscle. Several DOCK proteins have been implicated in maintaining several myogenic processes such as fusion. We previously identified DOCK3 as being strongly upregulated in Duchenne muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patients and dystrophic mice. Dock3 ubiquitous KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. We generated Dock3 conditional skeletal muscle knockout mice ( Dock3 mKO) to characterize the role of DOCK3 protein exclusively in the adult muscle lineage. Dock3 mKO mice presented with significant hyperglycemia and increased fat mass, indicating a metabolic role in the maintenance of skeletal muscle health. Dock3 mKO mice had impaired muscle architecture, reduced locomotor activity, impaired myofiber regeneration, and metabolic dysfunction. We identified a novel DOCK3 interaction with SORBS1 through the C-terminal domain of DOCK3 that may account for its metabolic dysregulation. Together, these findings demonstrate an essential role for DOCK3 in skeletal muscle independent of DOCK3 function in neuronal lineages.

Neuromuscular disorders (NMDs) are a group of rare diseases that largely affect the muscles, peripheral nervous system and neuromuscular junctions. Several genetic variations are associated with various types of NMDs. The fatal consequences of NMDs include skeletal muscle waste, reduction in muscle strength, muscle degeneration, neuropathy, spinal cord and neuromuscular junction abnormalities, sensory and motor impairment, lack of mobility and/ or defects in heart and lungs (Miller, 2008; Vissing, 2024; Zambon et al., 2024). The clinical diagnosis and the clinical management of NMDs in children and adults is very challenging since the majority of NMDs patients present unspecific clinical and pathological features that are similar between NMD sutypes (Mary et al., 2018; Angelini, 2012). The current diagnostic approaches include genetic testing, biochemical evaluation, muscle and nerve biopsy, computerized tomography, electromyography and magnetic resonance imaging (Holm et al., 2022; Ravi et al., 2019; Dabaj et al., 2024; Rathore and Kang, 2023). Technological progress has greatly improved our ability to diagnosed patients affected with NMDs; however, the majority are still very limited treatment options (Mackels and Servais, 2024). As an example, Duchenne muscular dystrophy patients have been treated with corticosteroids which exhibit detrimental adverse effects such as weight gain, behavioral problems and fragile bones. As for modeling of diseases, there are currently no efficient animal models to recapitulate key phenotypes seen in most NMDs patients. Absence of animal models further hinders the drug development for NMDs. Therefore, therapeutic strategies aimed at curing these NMDs efficiently are warranted now. The drug discovery and development approaches including gene editing, drug repurposing, RNA-based intervention and gene replacement therapy have greatly helped toward clinical trials and other drug developmental phases conducted for various NMDs. In the current scenario, creating novel animal models, gene therapy and biomarkers for NMDs have been on the rise as it may be beneficial in understanding