ArticleJournal of cachexia, sarcopenia and muscle2026
Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
Article in Journal of cachexia, sarcopenia and muscle, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundHeme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states.
methodsWe generated Hmox1/2 double-knockout mice (Hmox1/2
resultsHO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2
conclusionsHO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.
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