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Abstract
To test the role of extracellular-signal regulated kinases 1 and 2 (ERK1/2) in slow-twitch, type 1 skeletal muscle fibers, we studied the soleus muscle in mice genetically deficient for myofiber ERK1/2. Young adult mutant soleus was drastically wasted, with highly atrophied type 1 fibers, denervation at most synaptic sites, induction of “fetal” acetylcholine receptor gamma subunit (AChRγ), reduction of “adult” AChRε, and impaired mitochondrial biogenesis and function. In weanlings, fiber morphology and mitochondrial markers were mostly normal, yet AChRγ upregulation and AChRε downregulation were observed. Synaptic sites with fetal AChRs in weanling muscle were ~3% in control and ~40% in mutants, with most of the latter on type 1 fibers. These results suggest that: (1) ERK1/2 are critical for slow-twitch fiber growth; (2) a defective γ/ε-AChR subunit switch, preferentially at synapses on slow fibers, precedes wasting of mutant soleus; (3) denervation is likely to drive this wasting, and (4) the neuromuscular synapse is a primary subcellular target for muscle ERK1/2 function in vivo.
Highlights
Extracellular signal-regulated kinases 1 and 2 (ERK1/2), the prototypical mitogen-activated protein kinases, mediate a multitude of responses to growth factors and cytokines in cellular proliferation, differentiation, senescence, apoptosis, and survival[6]
Cre was driven by the human α-skeletal muscle actin (Hsa) promoter, which is expressed only in myofibers, and not in other cells in the muscle tissue, starting around embryonic day 9.513–15
SOD2, a mitochondrial protein that is a direct downstream target of PCG-1αregulation[31], was reduced ~40% in DKO SOL (p = 0.009; Fig. 6c). These results suggest that absence of muscle extracellular-signal regulated kinases 1 and 2 (ERK1/2) in the SOL leads to reduced mitochondrial biogenesis, which may account, at least in part, for the lower oxidative capacity reflected by the decrease in cytochrome oxidase (COX) and succinate dehydrogenase (SDH) activities
Summary
Extracellular signal-regulated kinases 1 and 2 (ERK1/2), the prototypical mitogen-activated protein kinases, mediate a multitude of responses to growth factors and cytokines in cellular proliferation, differentiation, senescence, apoptosis, and survival[6]. In STN, but not TA, we documented morphological and molecular evidence of partial denervation (e.g. terminal axonal sprouting and induction of the fetal AChRγ-subunit mRNA, respectively) Both muscles displayed a mixture of fiber loss and mild atrophy, but minimal changes in fiber-type composition. At three weeks after birth, control and mutant muscles were similar in fiber morphology, we found evidence of nascent denervation and a defective γ/ε-AChR subunit switch predominantly at NMJs on type 1 fibers. This suggests synaptic instability precedes extrasynaptic changes in myofibers lacking ERK1/2 in SOL. These results support the notion that the synapse is a primary subcellular target for muscle ERK1/2 function in vivo
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