Abstract
MAPK signaling consists of an array of successively acting kinases. ERK1 and -2 (ERK1/2) are major components of the greater MAPK cascade that transduce growth factor signaling at the cell membrane. Here, we investigated ERK1/2 signaling in skeletal muscle homeostasis and disease. Using mouse genetics, we observed that the muscle-specific expression of a constitutively active MEK1 mutant promotes greater ERK1/2 signaling that mediates fiber-type switching to a slow, oxidative phenotype with type I myosin heavy chain expression. Using a conditional and temporally regulated Cre strategy, as well as Mapk1 (ERK2) and Mapk3 (ERK1) genetically targeted mice, MEK1-ERK2 signaling was shown to underlie this fast-to-slow fiber-type switching in adult skeletal muscle as well as during development. Physiologic assessment of these activated MEK1-ERK1/2 mice showed enhanced metabolic activity and oxygen consumption with greater muscle fatigue resistance. In addition, induction of MEK1-ERK1/2 signaling increased dystrophin and utrophin protein expression in a mouse model of limb-girdle muscle dystrophy and protected myofibers from damage. In summary, sustained MEK1-ERK1/2 activity in skeletal muscle produces a fast-to-slow fiber-type switch that protects from muscular dystrophy, suggesting a therapeutic approach to enhance the metabolic effectiveness of muscle and protect from dystrophic disease.
Highlights
Myofibers are individual contractile units that compromise all muscles
The increase in total ERK1 and -2 (ERK1/2) protein observed in the Rosa26-MEK1Myl1–cre skeletal muscle-specific mice was previously observed in cardiac-specific MEK1-transgenic mice [24]
Early growth response protein 1 (EGR1) levels were increased in skeletal muscle with greater active MEK1 expression relative to controls suggesting that this branch of the ERK1/2 pathway was active
Summary
Myofibers are individual contractile units that compromise all muscles They are grossly categorized as type I slow-twitch oxidative myofibers, type IIA fast-twitch oxidative-glycolytic myofibers, or type IIB/IIX fast-twitch glycolytic myofibers [1]. These fiber types have distinct molecular and functional properties and can be identified at the histological level by expression of specific myosin heavy chain (MyHC) isoforms and selected metabolic genes. The desire to better understand the molecular mechanisms regulating fast-to-slow myofiber switching has been fueled by the potential therapeutic value of a more oxidative metabolic state in chronic diseases such as obesity and type 2 diabetes mellitus [2]. Potent regulators of the slow, oxidative program include the calcineurin-signaling pathway [5, 6], the AMPK [7], the PPAR β/δ pathway [8], as well as the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) pathway [9]
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