Background: DOCK (dedicator of cytokinesis) are proteins of an 11-member family of typical guanine exchange factors (GEFs) with many DOCKs expressed in skeletal muscle and neuronal lineages. Human DOCK3 pathogenic variants have been shown to cause debilitating neuromuscular phenotypes such as muscle hypotonia, ataxia, and intellectual disability. We previously identified DOCK3 as being strongly upregulated in Duchene muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patients and mice. Global Dock3 KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. Similarly, Dock3 global KO mice alone have poor muscle architecture, locomotive activity, reduced myogenic fusion, impaired glucose processing, and impaired muscle regeneration.
Hypothesis: The muscle-specific genetic loss of Dock3 will significantly reduce muscle function, regeneration, and myogenic fusion.
Methods: We generated a novel Dock3 muscle knockout (Dock3 mKO) mouse model by mating our Dock3 flox/flox conditional mouse model to the Human Skeletal Actin-MerCreMer (HSA-MCM) to delineate the muscle-specific role for DOCK3. We evaluated our muscle-specific Dock3 conditional KO mice using multiple locomotor and regenerative models in order to understand the skeletal and metabolic impact due to the loss of DOCK3 apart from its role in the central nervous system.
Results: Dock3 muscle KO mice had poor muscle architecture characterized by myofiber grouping of smaller fibers. Dock3 muscle KO mice also had impaired muscle function and performance as assessed through a battery of physiological examinations.
Conclusions: DOCK3 is required for normal muscle function and overall performance. The genetic loss of Dock3 in muscle, results in impaired muscle function and myogenesis. Further examination of DOCK3-interacting partners will likely yield insight into the mechanism of DOCK3 function in muscle.