Skeletal muscle plays a central role in whole-body energy expenditure and metabolic homeostasis, and improving its mitochondrial function and oxidative fiber profile is considered an effective strategy to counteract diet-induced metabolic impairments, although the molecular regulators of these adaptations are not yet fully understood. Erk3 has been implicated in myotube differentiation and in skeletal muscle adaptations to aerobic exercise; however, its potential role in skeletal muscle during diet-induced metabolic dysfunction remains to be determined. In this study, we used mice with striated muscle-specific Erk3 deletion alongside in vitro cultured myotubes, integrating metabolic phenotyping, indirect calorimetry, multi-omics profiling, and analyses of muscle morphology and fiber-type composition. Deletion of Erk3 in striated muscle protected mice from diet-induced obesity, glucose intolerance, and insulin resistance, accompanied by increased energy expenditure and elevated mitochondrial content. In cultured myotubes, silencing Erk3 or its putative interaction partner Mapkapk5 (Mk5) enhanced mitochondrial respiration and mitochondrial abundance, particularly under lipid overload. Global transcriptomic and proteomic analyses in myotubes deficient for either Erk3 or Mk5 revealed largely distinct molecular signatures for both kinases. However, consistent with increased oxidative respiration in the absence of Erk3 or Mk5, markers of oxidative fiber types were elevated while glycolic-fiber-specific proteins were diminished in the absence of one or the other kinase. Consistent with these findings, high-fat diet-fed Erk3-deficient mice showed fewer centrally located nuclei and were protected from the fiber-type remodeling associated with metabolic dysfunction. Our study demonstrates that Erk3 is a key regulator of skeletal muscle oxidative remodeling and metabolic resilience. The deletion of Erk3 in muscles promotes energy expenditure in the myotubes by enhancing mitochondrial function and shifting fiber identity toward oxidative types. Thus, deletion of this kinase protects against high-fat diet–induced obesity, glucose intolerance, and insulin resistance. • Muscle-specific Erk3 deletion enhances energy expenditure and protects from diet-induced metabolic dysfunction • Erk3 deletion increases mitochondrial function and oxidative fiber identity • Erk3 and Mapkapk5 shape muscle metabolic programs through distinct pathways
Loza-Valdes et al. (Sun,) studied this question.