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Changes in Skeletal Muscle PAK1 Levels Regulate Tissue Crosstalk to Impact Whole Body Glucose Homeostasis
Karla E Merz1, Ragadeepthi Tunduguru2, Miwon Ahn1
1Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute of City of Hope, Duarte, CA, United States.
Abstract:
Skeletal muscle accounts for ~80% of insulin-stimulated glucose uptake. The Group I p21-activated kinase 1 (PAK1) is required for the non-canonical insulin-stimulated GLUT4 vesicle translocation in skeletal muscle cells. We found that the abundances of PAK1 protein and its downstream effector in muscle, ARPC1B, are significantly reduced in the skeletal muscle of humans with type 2 diabetes, compared to the non-diabetic controls, making skeletal muscle PAK1 a candidate regulator of glucose homeostasis. Although whole-body PAK1 knockout mice exhibit glucose intolerance and are insulin resistant, the contribution of skeletal muscle PAK1 in particular was unknown. As such, we developed inducible skeletal muscle-specific PAK1 knockout (skmPAK1-iKO) and overexpression (skmPAK1-iOE) mouse models to evaluate the role of PAK1 in skeletal muscle insulin sensitivity and glucose homeostasis. Using intraperitoneal glucose tolerance and insulin tolerance testing, we found that skeletal muscle PAK1 is required for maintaining whole body glucose homeostasis. Moreover, PAK1 enrichment in GLUT4-myc-L6 myoblasts preserves normal insulin-stimulated GLUT4 translocation under insulin resistance conditions. Unexpectedly, skmPAK1-iKO also showed aberrant plasma insulin levels following a glucose challenge. By applying conditioned media from PAK1-enriched myotubes or myoblasts to β-cells in culture, we established that a muscle-derived circulating factor(s) could enhance β-cell function. Taken together, these data suggest that PAK1 levels in the skeletal muscle can regulate not only skeletal muscle insulin sensitivity, but can also engage in tissue crosstalk with pancreatic β-cells, unveiling a new molecular mechanism by which PAK1 regulates whole-body glucose homeostasis.
Insights
p21-activated kinase 1 (PAK1) in skeletal muscle is crucial for glucose uptake and insulin sensitivity. Reduced PAK1 in type 2 diabetes impacts glucose homeostasis and may affect pancreatic beta-cell function.
Area of Science:
- Metabolism
- Endocrinology
- Molecular Biology
Background:
- Skeletal muscle is the primary site of insulin-stimulated glucose uptake (~80%).
- Group I p21-activated kinase 1 (PAK1) is essential for insulin-stimulated GLUT4 vesicle translocation in muscle.
- Reduced PAK1 and ARPC1B protein levels are observed in type 2 diabetic human skeletal muscle, suggesting a role in glucose homeostasis.
Purpose of the Study:
- To investigate the specific role of skeletal muscle PAK1 in regulating insulin sensitivity and whole-body glucose homeostasis.
- To elucidate the molecular mechanisms by which skeletal muscle PAK1 influences glucose metabolism and potentially interacts with other tissues.
Main Methods:
- Development of inducible skeletal muscle-specific PAK1 knockout (skmPAK1-iKO) and overexpression (skmPAK1-iOE) mouse models.
- Intraperitoneal glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed.
- In vitro studies using myoblasts and β-cells were conducted to assess GLUT4 translocation and cell function.
Main Results:
- Skeletal muscle PAK1 is essential for maintaining whole-body glucose homeostasis.
- PAK1 enrichment in myoblasts improved insulin-stimulated GLUT4 translocation under insulin resistance conditions.
- skmPAK1-iKO mice exhibited aberrant plasma insulin levels, suggesting an impact on pancreatic β-cell function.
- Conditioned media from PAK1-enriched muscle cells enhanced β-cell function, indicating a muscle-derived circulating factor.
Conclusions:
- Skeletal muscle PAK1 plays a critical role in regulating insulin sensitivity and glucose homeostasis.
- PAK1 in skeletal muscle influences pancreatic β-cell function through potential muscle-derived circulating factors, highlighting a novel mechanism for whole-body glucose regulation.
- These findings identify skeletal muscle PAK1 as a key player in inter-organ communication impacting metabolic health.
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