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<p>Aerobic exercise improves systemic insulin sensitivity by modulating muscle glucose metabolism. The CHRONO/BMAL1 pathway constitutes a core component of the endogenous molecular clock and participates in glucose metabolic regulation; however, whether it mediates exercise-induced metabolic benefits under high-fat diet (HFD) conditions remains unclear. We therefore investigated the role of this pathway in conferring protective effects of aerobic exercise against HFD-induced glucose metabolic dysfunction in skeletal muscle, by subjecting wild-type (WT) and inducible muscle-specific <i>Chrono</i> overexpression (<i>Chrono</i> IMOE) mice to an HFD with or without 12-week exercise. Unlike in WT mice, exercise failed to ameliorate adipose mass, dyslipidemia, and insulin resistance in HFD-fed <i>Chrono</i> IMOE mice. Mechanistically, in skeletal muscle of <i>Chrono</i> IMOE mice, <i>Chrono</i> overexpression suppressed exercise-induced reductions in CHRONO expression and CHRONO-BMAL1 binding, as well as the increase in BMAL1 levels. Consequently, despite elevated p-TBC1D1<sup>Ser237</sup> and GLUT4 expression, exercise failed to promote GLUT4 sarcolemmal colocalization or upregulate gene expression of key enzymes for glycolysis and glycogen metabolism in skeletal muscle of <i>Chrono</i> IMOE mice. These findings demonstrate that preventing CHRONO‑BMAL1 dissociation via muscle-specific <i>Chrono</i> overexpression abrogates exercise-induced GLUT4 membrane trafficking, transcriptional activation of glycolytic/glycogen metabolic genes, and systemic insulin sensitivity improvements in HFD-fed mice, establishing CHRONO‑BMAL1 dissociation as a required step for these exercise adaptations.</p>

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Chrono overexpression blunts exercise-induced improvement in muscular glucose metabolism by inhibiting the BMAL1 transcriptional activity in high-fat diet-fed mice

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Lei Xu,
  • Jie Jia,
  • Lu Yan,
  • Yangwenjie Wang,
  • Shudan Miao,
  • Ying Zhang

摘要

Aerobic exercise improves systemic insulin sensitivity by modulating muscle glucose metabolism. The CHRONO/BMAL1 pathway constitutes a core component of the endogenous molecular clock and participates in glucose metabolic regulation; however, whether it mediates exercise-induced metabolic benefits under high-fat diet (HFD) conditions remains unclear. We therefore investigated the role of this pathway in conferring protective effects of aerobic exercise against HFD-induced glucose metabolic dysfunction in skeletal muscle, by subjecting wild-type (WT) and inducible muscle-specific Chrono overexpression (Chrono IMOE) mice to an HFD with or without 12-week exercise. Unlike in WT mice, exercise failed to ameliorate adipose mass, dyslipidemia, and insulin resistance in HFD-fed Chrono IMOE mice. Mechanistically, in skeletal muscle of Chrono IMOE mice, Chrono overexpression suppressed exercise-induced reductions in CHRONO expression and CHRONO-BMAL1 binding, as well as the increase in BMAL1 levels. Consequently, despite elevated p-TBC1D1Ser237 and GLUT4 expression, exercise failed to promote GLUT4 sarcolemmal colocalization or upregulate gene expression of key enzymes for glycolysis and glycogen metabolism in skeletal muscle of Chrono IMOE mice. These findings demonstrate that preventing CHRONO‑BMAL1 dissociation via muscle-specific Chrono overexpression abrogates exercise-induced GLUT4 membrane trafficking, transcriptional activation of glycolytic/glycogen metabolic genes, and systemic insulin sensitivity improvements in HFD-fed mice, establishing CHRONO‑BMAL1 dissociation as a required step for these exercise adaptations.