Dock7 is an essential driver of Skeletal Muscle Health and Function


Translational Research

Poster Number: 308


Katherine English, University of Alabama at Birmingham, Adrienne Samani, PhD, University of Alabama at Birmingham, Muthukumar Karuppasamy, PhD, University of Alabama at Birmingham, Matthew Alexander, PhD, University of Alabama at Birmingham

Background: Members of 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) pathologies. Following a similar disease pattern, DOCK7 expression is upregulated in both human DMD muscle biopsies and multiple DMD mouse models. DOCK7 primarily activates 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: : We hypothesized that DOCK7 plays an integral role in skeletal muscle health and function through its promotion of RAC1 signaling and that impaired muscle function due to DOCK7-deficiency, modeled with Dock7 conditional muscle knockout (KO) mice, can be ameliorated by constitutive skeletal muscle RAC1 activation.

Methods: We have generated Dock7 muscle KO mice (Dock7 mKO) and Dock7 motor neuron KO (Dock7 mnKO) by mating our Dock7 flox/flox conditional mice with our HSA-Cre (mKO; myofiber knockout) transgenic, and vChAT Cre (mnKO; motor neuron knockout) drivers. We have performed systemic evaluations of the Dock7 mKO and mnKO mouse histology, muscle performance, molecular transcriptomes, and overall function.

Results: Dock7 mKO mice have impaired grip strength, locomotive activity, muscle architecture, and overall muscle deficits compared to WT controls. DOCK7 knockout muscle also has impaired RAC1 pathway dynamics. Preliminary data indicates Dock7 mnKO mice have more severe neuromuscular deficits than the Dock7 mKO mice.

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.