Cover Story Current Issue
Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.
Current Issue
Erk3 deletion drives oxidative adaptations in skeletal muscle
Erk3 deletion drives oxidative adaptations in skeletal muscle
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Articles in Press
Erk3 deletion drives oxidative adaptations in skeletal muscle
Erk3 deletion drives oxidative adaptations in skeletal muscle
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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