The molecular mechanisms controlling -adrenergic receptor agonist (BA)-induced skeletal muscle hypertrophy are not well known. We presently report that BA exerts a distinct muscle-and muscle fiber type-specific hypertrophy. Moreover, we have shown that pharmacologically or genetically attenuating extracellular signal-regulated kinase (ERK) signaling in muscle fibers resulted in decreases (P Ͻ 0.05) in fast but not slow fiber type-specific reporter gene expressions in response to BA exposure in vitro and in vivo. Consistent with these data, forced expression of MAPK phosphatase 1, a nuclear protein that dephosphorylates ERK1/2, in fast-twitch skeletal muscle ablated (P Ͻ 0.05) the hypertrophic effects of BA feeding (clenbuterol, 20 parts per million in water) in vivo. Further analysis has shown that BA-induced phosphorylation and activation of ERK occurred to a greater (P Ͻ 0.05) extent in fast myofibers than in slow myofibers. Analysis of the basal level of ERK activity in slow and fast muscles revealed that ERK1/2 is activated to a greater extent in fast-than in slow-twitch muscles. These data indicate that ERK signaling is differentially involved in BA-induced hypertrophy in slow and fast skeletal muscles, suggesting that the increased abundance of phospho-ERK1/2 and ERK activity found in fast-twitch myofibers, compared with their slow-twitch counterparts, may account, at least in part, for the fiber type-specific hypertrophy induced by BA stimulation. These data suggest that fast myofibers are pivotal in the adaptation of muscle to environmental cues and that the mechanism underlying this change is partially mediated by the MAPK signaling cascade. muscle fiber type; mitogen-activated protein kinase signaling pathways; mechanism SKELETAL MUSCLE ADAPTATION is triggered by a variety of cues that depend largely on a delicate balance between hypertrophy and atrophy signaling processes converging on the nucleus (34,37,39). This delicate balance suggests that hypertrophy may provide a means to antagonize skeletal muscle atrophy induced by some physiological and pathological challenges (16). -Adrenergic agonists (BA) are a family of compounds that induce skeletal muscle hypertrophy in rats (7, 13, 46), mice (21), pigs (12), cattle, and sheep (27). Consistent with the aforementioned thesis, BA antagonize skeletal muscle atrophy in experimentally induced denervation or limb immobilization models (11, 21). Mechanistically, BA bind to the -adrenergic receptor, a G protein-coupled receptor, and activate the G s protein and PKA signaling pathway. PKA then phosphorylates the -receptor and switches its coupling from G s to G i protein. The ␥-subunit of G i protein stimulates the ERK-MAPK through a pathway involving c-Src and Ras (10). The activated receptor is then phosphorylated and bound by -arrestin for degradation, a process called desensitization (29,38). Modulation of receptor desensitization is thought to account for the activation of MAPK in isoproterenol-stimulated cells (24). In addition, the  2 form of the ...
Skeletal muscle is composed of diverse fiber types, yet the underlying molecular mechanisms responsible for this diversification remain unclear. Herein, we report that the extracellular signal-regulated kinase (ERK) 1/2 pathway, but not p38 or c-Jun NH(2)-terminal kinase (JNK), is preferentially activated in fast-twitch muscles. Pharmacological blocking of ERK1/2 pathway increased slow-twitch fiber type-specific reporter activity and repressed those associated with the fast-twitch fiber phenotype in vitro. Overexpression of a constitutively active ERK2 had an opposite effect. Inhibition of ERK signaling in cultured myotubes increased slow-twitch fiber-specific protein accumulation while repressing those characteristic of fast-twitch fibers. Overexpression of MAP kinase phosphatase-1 (MKP1) in mouse and rat muscle fibers containing almost exclusively type IIb or IIx fast myosin heavy chain (MyHC) isoforms induced de novo synthesis of the slower, more oxidative type IIa and I MyHCs in a time-dependent manner. Conversion to the slower phenotype was confirmed by up-regulation of slow reporter gene activity and down-regulation of fast reporter activities in response to forced MKP1 expression in vivo. In addition, activation of ERK2 signaling induced up-regulation of fast-twitch fiber program in soleus. These data suggest that the MAPK signaling, most likely the ERK1/2 pathway, is necessary to preserve the fast-twitch fiber phenotype with a concomitant repression of slow-twitch fiber program.
The signal transduction cascades that maintain muscle mass remain to be fully defined. Herein, we report that inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in vitro decreases myotube size and protein content after 3-day treatment with a MEK inhibitor. Neither p38 nor JNK inhibitors had any effect on myotube size or morphology. ERK1/2 inhibition also upregulated gene transcription of atrogin-1 and muscle-specific RING finger protein 1 and downregulated the phosphorylation of Akt and its downstream kinases. Forced expression of enhanced green fluorescent protein-tagged MAPK phosphatase 1 (MKP-1) in soleus and gastrocnemius muscles decreased both fiber size and reporter activity. This atrophic effect of MKP-1 was time dependent. Analysis of the reporter activity in vivo revealed that the activities of nuclear factor-κB and 26S proteasome were differentially activated in slow and fast muscles, suggesting muscle type-specific mechanisms may be utilized. Together, these findings suggest that MAPK signaling is necessary for the maintenance of skeletal muscle mass because inhibition of these signaling cascades elicits muscle atrophy in vitro and in vivo.
Muscle contraction stimulates glucose transport independent of insulin. Glucose uptake into muscle cells is positively related to skeletal muscle-specific glucose transporter (GLUT-4) expression. Therefore, our objective was to determine the effects of the contraction-mediated signals, calcium and AMP-activated protein kinase (AMPK), on glucose uptake and GLUT-4 expression under acute and chronic conditions. To accomplish this, we used pharmacological agents, cell culture, and pigs possessing genetic mutations for increased cytosolic calcium and constitutively active AMPK. In C2C12 myotubes, caffeine, a sarcoplasmic reticulum calcium-releasing agent, had a biphasic effect on GLUT-4 expression and glucose uptake. Low-concentration (1.25 to 2 mM) or short-term (4 h) caffeine treatment together with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR), had an additive effect on GLUT-4 expression. However, high-concentration (2.5 to 5 mM) or long-term (4 to 30 h) caffeine treatment decreased AMPK-induced GLUT-4 expression without affecting cell viability. The negative effect of caffeine on AICAR-induced GLUT-4 expression was reduced by dantrolene, which desensitizes the ryanodine receptor. Consistent with cell culture data, increases in GLUT-4 mRNA and protein expression induced by AMPK were blunted in pigs possessing genetic mutations for both increased cytosolic calcium and constitutively active AMPK. Altogether, these data suggest that chronic exposure to elevated cytosolic calcium concentration blocks AMPK-induced GLUT-4 expression in skeletal muscle.
Dynamics of the ensiling process and final quality of whole-crop wheat, oats, and barley harvested at the milk and the dough stage of maturity were studied using 2.2-liter laboratory silos. An ensiling period of 64 d was used. Silage DM was higher (P less than .05) at the dough than at the milk stage on d 0 and 64. Silage total N content was not different (P greater than .05) among small grain species or stages of maturity either at harvest or 64 d after ensiling. Overall, buffering capacity (BC) on d 0 was greater (P less than .05) in oats and barley than in wheat silages. Small grains had a greater (P less than .05) BC when harvested in the milk stage than when harvested in the dough stage. In all silages, pH had declined (P less than .01) by d 64, when it ranged from 3.8 to 4.1. During the ensiling period, lactic acid concentrations increased (P less than .01) and ranged from 6 to 11% of DM by 64 d of ensiling. Water-soluble carbohydrate (WSC) content was greater (P less than .01) in milk- than in dough-stage silages for each small grain species and declined (P less than .05) during the ensiling period. The WSC decline during ensiling was greater (P less than .01) for milk-stage than for dough-stage harvested forage. Water-soluble N increased during ensiling (P less than .01) and increased 100 to 200% by d 64 for all silages. Ammonia N increased during the 64-d ensiling period but never exceeded .2% of DM.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of dietary vitamin E (VE, alpha-tocopherol acetate) and fat supplementation on growth and carcass quality characteristics, oxidative stability of fresh and cooked pork patty in storage, fatty acid profiles of muscle and adipose tissue, and VE concentrations of plasma, muscle, and adipose tissue were studied. Six hundred pigs were allocated to 1 of 6 diets and fed for 63 d in a 3 x 2 factorial design. The dietary treatments included 3 fat levels (normal corn, high oil corn, high oil corn plus added beef tallow) and 2 levels of VE supplementation (40 IU/kg, normal VE supplementation; and 200 IU/kg, high VE supplementation). At 113 kg of BW, 54 pigs were slaughtered as a subsample to evaluate dietary effects on pork quality. Growth performance and meat quality characteristics did not differ (P > 0.05) among treatment groups. The high level of VE supplementation had a beneficial effect on the oxidative stability of pork as indicated by thiobarbituric acid reactive substance (TBARS) values. Lean tissue had lower (P < 0.05) TBARS in the group fed the high VE than in those fed the normal VE level. The TBARS values differed among storage periods (0 to 6 d) and also between fresh and cooked ground ham. Fat type did not significantly affect total saturated and unsaturated fatty acids proportions in the neutral and polar fraction of muscle. Adding VE acetate led to greater (P < 0.05) monounsaturated and total unsaturated fatty acid proportions in neutral lipids of muscle and adipose tissues. Increasing dietary levels of VE acetate increased the concentration of VE in plasma and muscle. These results indicate that dietary VE acetate supplementation increased (P < 0.05) lipid stability and the VE concentration of muscle.
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