All ETDs from UAB

Advisory Committee Chair

Constanza Cortes

Advisory Committee Members

Matthew S Alexander

Sofia Beas

Farah Lubin

Anna Thalacker-Mercer

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

DOCK (dedicator of cytokinesis) are proteins of an 11-member family of typical guanine exchange factors (GEFs) expressed almost exclusively in the brain and spinal cord. Human pathogenic DOCK3 variants have been identified to cause debilitating neuromuscular phenotypes such as muscle hypotonia, ataxia, and intellectual disability. Our lab identified DOCK3 as being strongly upregulated in Duchene muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patient and mouse skeletal muscles. Global Dock3 KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. Similarly, DOCK3 KO mice appeared to have poor muscle architecture, locomotive activity, reduced myogenic fusion, impaired glucose processing, and impaired muscle regeneration. However, the understanding of Dock3 strictly in skeletal muscle and its distinct role in muscle function, metabolism, and myogenic processes is poorly understood and remains to be elucidated. I sought to elucidate the role of Dock3 in the skeletal muscle by 1) generating 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 a muscle-specific role for DOCK3. 2) I sought to characterize the effect of a novel 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 iii system. 3) I determined that Dock3 muscle KO mice had poor muscle architecture characterized by myofiber grouping of smaller fibers. 4) Dock3 muscle KO mice also had impaired muscle function and performance 5) I determined novel Dock3 protein-protein interaction with insulin adaptor protein, Sorbin SH3 domain-containing 1 (SORBS1) and it’s impact in skeletal muscle metabolic processing. Collectively, my work provides a thorough foundation for understanding a unique and understudied gene family and its role in adult skeletal muscle growth, regeneration, and metabolism. I believe this foundation will be key for follow-on analyses to further ascertain its impact on overall skeletal muscle health, as well as within other tissues such as the motor neuron, and provide critical insight on targeted pathways and therapeutic development for human disease.

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