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Muscle Fibers Utilize its Glucose Uptake Machinery to Reseal Sarcolemma Disruptions & Stimulating Affiliated Rab G Proteins Improves Repair Capacity in Muscle Dystrophic Mice
Author(s) -
Kwiatkowski Thomas A,
Rose Aubrey,
Jung Rachel,
McElha Kevin,
Paleo Brian,
Beck Eric X,
Weisleder Noah
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03329
Subject(s) - microbiology and biotechnology , glut4 , skeletal muscle , glucose transporter , myocyte , rab , glucose uptake , sarcolemma , c2c12 , biology , exocytosis , biochemistry , myogenesis , endocrinology , insulin , membrane , gtpase
The glucose uptake machinery in cells and muscle fibers is a robust and highly regulated system used to import extracellular glucose for intracellular metabolic processing. The majority of glucose uptake in skeletal muscle is done through stimulated exocytosis and fusion of vesicles to the plasma membrane to enrich the cellular exterior with glucose transporter protein GLUT4. In our investigation, we found evidence that GLUT4 containing vesicles (GSV) and the glucose uptake regulators AS160, rab8A, and rab10 serve an additional role in the plasma membrane repair response. Through the use of mutant plasmids and live cell imaging, we observed that GSVs, as well as affiliated rabs, translocate to injury sites in C2C12 myoblasts and isolated mouse muscle fibers under different modes of damage. We observed that AS160 phosphorylation from the phosphoinositide‐3 kinase (PI3K)/Akt1 signaling axis regulates membrane repair in cultured muscle cells. In addition, we screened GSV associating rab G proteins and saw that knocking down rab8A and rab10 expression reduced the repair capacity of the cells. Importantly, through the electroporation of overexpression or constitutively active rab10 mutant constructs in skeletal muscle of Duchenne muscular dystrophy mdx mice, there was a significant improvement in membrane resealing in vivo. Overall, our findings suggest that the glucose uptake vesicles commonly thought of as important for metabolic homeostasis, serve an additional function in repairing membrane wounds in some cell lines and mouse muscle fibers. Targeting glucose uptake regulators could lead to the development of new therapies for muscle disease and injury.