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ERK1/2 signaling induces skeletal muscle slow fiber-type switching and reduces muscular dystrophy disease severity.

ABSTRACT: Mitogen-activated protein kinase (MAPK) signaling consists of an array of successively acting kinases. The extracellular signal-regulated kinases 1/2 (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. Moreover, 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.

SUBMITTER: Boyer JG

PROVIDER: S-EPMC6542606 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity.

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The microRNA miR-133b functions to slow Duchenne muscular dystrophy pathogenesis.

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| S-EPMC4837049 | biostudies-literature

Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy.

Project description:We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI - 6.1, - 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI - 11.2, - 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI - 4.6, - 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI - 6.7, - 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL β = 0.003, 95% CI - 0.01 to 0.002, p = 0.72).Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD. What is Known • Severe growth impairment and short stature are commonly observed in boys with Duchenne muscular dystrophy (DMD), especially those treated with long-term glucocorticoids (GC). • In other groups of children with chronic conditions and/or disorders of puberty, skeletal disproportion with lower spinal length has been reported. What is New • Growth impairment in GC-treated boys with DMD was associated with skeletal disproportion in relation to age, with lower limbs and distal long bones affected to a greater degree.

| S-EPMC6459782 | biostudies-literature

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| S-EPMC5012513 | biostudies-literature

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