Glucose Sensing by Skeletal Myocytes Couples Nutrient Signaling to Systemic Homeostasis

Abstract

SUMMARY Skeletal muscle is a major site of postprandial glucose disposal. Inadequate insulin action in skeletal myocytes contributes to hyperglycemia in diabetes. While glucose is known to stimulate insulin secretion by β cells, whether it directly engages nutrient signaling pathways in skeletal muscle to maintain systemic glucose homeostasis remains largely unexplored. Here we identified the Baf60c-Deptor-AKT pathway as a target of muscle glucose sensing that augments insulin action in skeletal myocytes. Genetic activation of this pathway improved postprandial glucose disposal in mice, whereas its muscle-specific ablation impaired insulin action and led to postprandial glucose intolerance. Mechanistically, glucose triggers KATP channel-dependent calcium signaling that promotes HDAC5 phosphorylation and nuclear exclusion, leading to Baf60c induction and insulin-independent AKT activation. This pathway is engaged by the anti-diabetic drugs sulfonylureas to exert their full glucose-lowering effects. These findings uncover an unexpected mechanism of glucose sensing in skeletal myocytes that contributes to homeostasis and therapeutic action.

Metabolic‐sensing of the skeletal muscle clock coordinates fuel oxidation

“…Insulin induced by feeding could be a major clock input signal with its downstream signaling potentially modulating clock gene transcription, as our data suggest. Meng et al recently discovered an important direct glucose‐sensing mechanism in muscle mediated by a HDAC5‐Baf60c‐Deptor‐Akt cascade 44 . Our findings of insulin‐responsive Bmal1 induction may function synergistically with this pathway, in parallel or through cross‐talk between Bmal1 and Baf60c‐mediated transcription programs, to facilitate glucose disposal.…”

Nuclear receptor corepressor 1 represses cardiac hypertrophy

“…ChIP experiments were carried out using EZ‐ChIP kit (17‐371, Millipore). 5 μg anti‐NCoR1 antibodies (5948, Cell Signaling), 2 μg anti‐MEF2a antibodies (sc‐17785, Santa Cruz), 10 μg anti‐HDAC4 (ab12172, Abcam), 10 μg anti‐HDAC5 (ab1439, Abcam; Meng et al , ), 5 μg anti‐acetyl‐Histone H3 (06‐599, Millipore), 5 μg anti‐acetyl‐Histone H4 (06‐598, Millipore), 10 μg anti‐RNA polymerase II (05‐623B, Millipore), mouse IgG (12‐371B, Millipore), and rabbit IgG (2729, Cell Signaling) were used for the pulldowns. ChIP products were analyzed using PCR.…”

Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

“…Tightly regulated control of muscle metabolism is essential to performance and the well being of the whole organism (1)(2)(3). With exercise, muscle coordinately upregulates the metabolism of glucose, fatty acids, and amino acids for energy production, and this response varies with time of day (4).…”