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Updated: May 29, 2026
A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice
Published on: June 14, 2024
Hypoxia exacerbates mechanical disuse-induced muscle decline through structural, functional, and molecular
Rizwan Qaisar1,2,3, Megna Srinivas4,5, Firdos Ahmad1,2,3
1Department of Basic Medical Sciences, College of Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates.
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Prolonged physical inactivity, such as that occurring during bed rest, causes rapid skeletal muscle atrophy and weakness and is commonly modeled in rodents using hindlimb unloading (HU). In clinical settings, however, unloading often coexists with systemic hypoxia due to cardiopulmonary disease. Despite separate studies of unloading and hypoxia, HU models are largely normoxic, limiting insight into hypoxia‑modified muscle decline. Addressing this gap is important for improving the translational relevance of inactivity-induced muscle atrophy models. We investigated the effects of HU under normoxic and hypoxic conditions by exposing male C57BL/6J mice to HU or ground‑control conditions under normoxia or 15% hypoxia for three weeks. Body weight, gastrocnemius muscle mass, morphology, and grip strength were quantified. Transcriptomic changes in the gastrocnemius muscle were analyzed by RNA sequencing. HU reduced gastrocnemius muscle mass and single fiber cross-sectional area, which were further amplified by hypoxia. Hypoxia also increased myonuclei count per fiber and reduced myonuclear domain size of individual fibers, independent of HU. Hypoxia and HU exhibited a significant interaction in reducing the absolute and normalized grip strengths of four paws. Transcriptomic analysis revealed extensive molecular reprogramming in hypoxic HU muscle, with more than 900 differentially expressed genes, uniquely regulated under combined HU and hypoxia. Enriched pathways included extracellular matrix remodeling, inflammatory signaling, bioenergetic metabolism, protein turnover, and cytoskeletal regulation, with prominent upregulation of genes associated with cilia, centrosome, and microtubule organization. Hypoxia exacerbates inactivity-induced muscle atrophy by selectively impairing muscle quality and inducing extensive transcriptional reprogramming.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s13205-026-04854-4.
