Abstract
DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression of DOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. By utilizing Dock3 global knockout (Dock3 KO) mice, we found reducing Dock3 gene via haploinsufficiency in DMD mice improved dystrophic muscle histology, however complete loss of Dock3 worsened overall muscle function on a dystrophin-deficient background. Consistent with this, Dock3 KO mice have impaired muscle architecture and myogenic differentiation defects. Moreover, transcriptomic analyses of Dock3 knockout muscles reveal a decrease in factors known for myogenesis, suggesting a possible mechanism of action. These studies identify DOCK3 as a novel modulator of muscle fusion and muscle health and may yield additional therapeutic targets for treating dystrophic muscle symptoms.
Footnotes
↵† Co-first author
Emails of Authors: areid01{at}uab.edu, ywang{at}peds.uab.edu, asamani{at}uab.edu, rylieh{at}uab.edu, mlopez{at}peds.uab.edu, srgilbert{at}uabmc.edu, lianov{at}uab.edu, dkcrossm{at}uab.edu, ldellitalia{at}uabmc.edu, douglas.millay{at}cchmc.org, vangroen{at}uab.edu, ghalade{at}usf.edu
↵* malexander{at}peds.uab.edu
List of Abbreviations
- CSA
- cross-sectional area
- ctx
- cardiotoxin
- DAPC
- dystrophin-associated complex
- DEXA
- dual energy x-ray absorptiometry
- DIG
- digoxigenin-UTP
- DMD
- Duchenne muscular dystrophy
- DOCK
- Dedicator of cytokinesis
- dpf
- days post fertilization
- ECM
- extracellular matrix
- GEF
- guanine nucleotide exchange factor
- GFP
- green fluorescent protein
- GRMD
- Golden retriever muscular dystrophy
- GTT
- glucose tolerance test
- ISH
- in situ hybridization
- MLPA
- multiplex ligation-dependent probe amplification
- MOCA
- modifier of cellular adhesion
- MO
- morpholino
- MyHC
- Myosin Heavy Chain
- PTU
- 1-Phenyl-2-Thiourea; N-Phenylthiourea
- QMR
- Quantitative Magnetic Resonance
- qPCR
- quantitative polymerase chain reaction
- shRNA
- short hairpin RNA
- siRNA
- small interfering RNA
- TA
- tibialis anterior