Changes in Skeletal Muscle PAK1 Levels Regulate Tissue Crosstalk to Impact Whole Body Glucose Homeostasis

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.

Characterization and comparative transcriptomic analysis of skeletal muscle in female Pekin duck and Hanzhong Ma duck during different growth stages using RNA-seq

“…In the fusion of myoblasts in Drosophila , group I PAK has partial redundant functions, with the close homolog of mammalian PAK2 , DPak3, playing a major role in this process ( Duan et al, 2012 ). Recent studies have evaluated the role of PAK1 in insulin sensitivity and glucose homeostasis in skeletal muscle, and found that PAK1 in skeletal muscle is essential for maintaining systemic glucose homeostasis ( Merz et al, 2022 ). The lack of muscle specificity in PAK1 and PAK2 can lead to a decrease in muscle mass, indicating that PAK1 and PAK2 play an important role in muscle.…”

Critical Differential Expression Assessment for Individual Bulk RNA-Seq Projects

“…There are currently two main topics contained within the Supplemental Results. First, rationale for the study and citation of other previously published studies using templates related to this study are described (Supplemental Table S3, [85][86][87][88][89][90][91][92]). Second, a limited number of comparisons on downstream enrichment results is provided (Supplemental Table S4, [26,70,71,73]).…”

Involvement of the extracellular matrix and integrin signalling proteins in skeletal muscle glucose uptake

“…Upon stimulation, GLUT4s translocate from GLUT storage vesicles in the cytoplasm to the cell surface to facilitate glucose uptake across the sarcolemma (Sylow et al., 2021 ). The processes involved in GLUT4 trafficking have received a great deal of attention and have been reviewed elsewhere (McConell et al., 2020 ; Merz et al., 2022 ; Richter, 2021 ; Richter & Hargreaves, 2013 ; Sylow et al., 2017 , 2021 ; Tunduguru & Thurmond, 2017 ), and therefore they will only be briefly outlined within this review.…”