Background: Members in the Dedicator of cytokinesis (DOCK) family of atypical GEFs have critical roles in muscle fusion and regeneration, including DOCK1, DOCK3, and DOCK5. Our lab has previously demonstrated that DOCK3 is a dosage sensitive modifier of Duchenne muscular dystrophy (DMD) pathology. Following the same pattern, DOCK7 expression is upregulated in both human DMD muscle biopsies and multiple mouse models of DMD. DOCK7 activates primarily RAC1, subsequently suggesting it plays an important role in RAC1 pathway activation. Human loss-of-function DOCK7 pathogenic variants result in muscle hypotonia in addition to neuronal co-morbidities consisting of epileptic encephalopathy, intellectual disability, and developmental delay.
Hypothesis: Dock7 is essential for normal skeletal muscle function and that its absence, modeled with Dock7 conditional muscle knockout (KO) mice, will result in impaired muscle regeneration and migration likely due its interactions with RAC1 and the cytoskeleton.
Methods: We generated Dock7 muscle KO mice (Dock7 mKO) by mating our Dock7 flox/flox conditional mice with both inducible (+/- tamoxifen; HSA-MerCreMer) and non-inducible (HSA-Cre) transgenic Cre drivers. We performed systemic evaluations of the Dock7 muscle KO mouse histology, muscle performance, molecular transcriptomes, and overall function.
Results: Dock7 muscle KO mice have impaired grip strength, locomotive activity, muscle architecture, and overall muscle deficits compared to WT controls. Dock7 knockout muscle has impaired RAC1 pathway dynamics.
Conclusions: Dock7 is essential for normal muscle function, structure, and overall performance. Genetic disruption of the DOCK7-RAC1 protein-protein interaction results in RAC1 pathway disruption and a failure to properly activate RAC1 in DOCK7-deficient muscle.