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Skeletal muscles continuously produce ATP to provide the energy that enables muscle contractions. Skeletal muscle fibers can be categorized into three types based on differences in their contraction speed and how they produce ATP, as well as physical differences related to these factors. Most human muscles contain all three muscle fiber types, albeit in varying proportions.
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Skeletal muscles are composed of a bundle of muscle fibers and are attached to bones through tendons. Each skeletal muscle fiber is a single muscle cell. The sarcolemma, the plasma membrane of a skeletal muscle cell, consists of a lipid bilayer and glycocalyx that supports muscle fibers. The sarcolemma extends into the muscle cells to form tubular structures called transverse or T-tubules. Each side of the T-tubules consists of a membrane-bound structure called the sarcoplasmic reticulum,...
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The clinical conditions affecting the skeletal muscle tissue are broadly categorized as musculoskeletal and neuromuscular disorders.
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Transcriptomic analyses reveal rhythmic and CLOCK-driven pathways in human skeletal muscle.

Laurent Perrin1,2,3,4, Ursula Loizides-Mangold1,2,3,4, Stéphanie Chanon5

  • 1Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.

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The body's internal clock (circadian rhythm) significantly influences skeletal muscle metabolism. Disrupting this clock impairs glucose and lipid utilization, highlighting its importance for human metabolic health.

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Area of Science:

  • * Chronobiology
  • * Molecular biology
  • * Human physiology

Background:

  • * Circadian rhythms regulate gene expression and cellular metabolism.
  • * Skeletal muscle plays a crucial role in glucose and lipid homeostasis.
  • * Understanding the diurnal regulation of skeletal muscle metabolism is vital for human health.

Purpose of the Study:

  • * To compare diurnal transcriptional patterns in human skeletal muscle in vivo versus in vitro.
  • * To investigate the impact of circadian clock disruption on skeletal muscle metabolism.
  • * To elucidate the role of circadian regulation in skeletal muscle glucose and lipid metabolism.

Main Methods:

  • * Comparison of diurnal transcriptomes from human skeletal muscle biopsies (in vivo) and synchronized myotubes (in vitro).
  • * siRNA-mediated disruption of the core clock gene, CLOCK, in primary human myotubes.
  • * Analysis of gene expression related to glucose and lipid metabolism, including GLUT4.
  • * Measurement of basal and insulin-stimulated glucose uptake.

Main Results:

  • * Human skeletal muscle exhibits more extensive rhythmic transcription in vivo than in vitro.
  • * Circadian clock disruption significantly altered ~8% of genes, impacting glucose and lipid metabolism.
  • * Genes involved in glucose transporter type 4 (GLUT4) were negatively affected.
  • * Lipid metabolic genes were altered to favor lipid utilization.
  • * CLOCK depletion reduced both basal and insulin-stimulated glucose uptake.

Conclusions:

  • * A significant portion of in vivo mRNA rhythmicity in skeletal muscle is lost in vitro.
  • * The circadian clock is essential for coordinating skeletal muscle glucose homeostasis and lipid metabolism in humans.
  • * Disruption of circadian regulation in skeletal muscle has detrimental effects on metabolic functions.