scholarly journals mTor Signaling in Skeletal Muscle During Sepsis and Inflammation: Where Does It All Go Wrong?

Physiology ◽  
2011 ◽  
Vol 26 (2) ◽  
pp. 83-96 ◽  
Author(s):  
Robert A. Frost ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Growth Factors ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Mtor Signaling ◽  
Evolutionarily Conserved ◽  
Control Protein

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that exquisitely regulates protein metabolism in skeletal muscle. mTOR integrates input from amino acids, growth factors, and intracellular cues to make or break muscle protein. mTOR accomplishes this task by stimulating the phosphorylation of substrates that control protein translation while simultaneously inhibiting proteasomal and autophagic protein degradation. In a metabolic twist of fate, sepsis induces muscle atrophy in part by the aberrant regulation of mTOR. In this review, we track the steps of normal mTOR signaling in muscle and examine where they go astray in sepsis and inflammation.

scholarly journals Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK

2013 ◽  
Vol 304 (10) ◽  
pp. E1042-E1052 ◽  
Author(s):  
James P. White ◽  
Melissa J. Puppa ◽  
Song Gao ◽  
Shuichi Sato ◽  
Stephen L. Welle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Glucose Administration ◽  
Mtorc1 Signaling ◽  
Dose Dependent ◽  
Mtor Activity

Although catabolic signaling has a well-established role in muscle wasting during cancer cachexia, the suppression of anabolic signaling also warrants further investigation. In cachectic tumor-bearing mice, circulating IL-6 levels are associated with suppressed muscle protein synthesis and mTORC1 signaling. We have found AMPK and IGF-I/insulin signaling, two well-known regulators of the mammalian target of rapamycin (mTOR), are altered with the progression of cachexia. How IL-6 can induce suppression of mTORC1 signaling remains to be established. The purpose of this study was to examine mTOR complex 1 (mTORC1) activation and regulation by IL-6 during cancer cachexia. IL-6 effects on mTOR activation were examined in Apc Min/+ mouse skeletal muscle and C2C12 myotubes. Systemic IL-6 overexpression in Apc Min/+ mice produced a dose-dependent suppression of mTOR signaling that corresponded to induction of STAT3 and AMPK phosphorylation. This result was also evident in IL-6-treated myotubes. Basal mTOR activation and mTOR responsiveness to glucose administration were suppressed in cachectic skeletal muscle. However, insulin induction of mTOR activity was maintained in IL-6-treated myotubes. Whereas IL-6 suppression of myotube mTOR activity was rescued by AMPK inhibition, inhibition of STAT3 signaling was not sufficient to rescue IL-6 suppression of mTOR activity. Last, treadmill exercise training was able to prevent IL-6-induced inhibition of mTOR signaling in Apc Min/+ mice independently of activated STAT. In conclusion, we report dose-dependent suppression of mTOR activity by IL-6 and suppressed mTOR responsiveness to glucose administration in Apc Min/+ mice. IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes.

scholarly journals Alcohol impairs skeletal muscle protein synthesis and mTOR signaling in a time-dependent manner following electrically stimulated muscle contraction

2014 ◽  
Vol 117 (10) ◽  
pp. 1170-1179 ◽  
Author(s):  
Jennifer L. Steiner ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Saline Control ◽  
Dependent Manner ◽  
Skeletal Muscle Protein

Alcohol (EtOH) decreases protein synthesis and mammalian target of rapamycin (mTOR)-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute EtOH intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male mice were injected intraperitoneally with 3 g/kg EtOH or saline (control), and the right hindlimb was electrically stimulated (10 sets of 6 contractions). The gastrocnemius muscle complex was collected 30 min, 4 h, or 12 h after stimulation. EtOH decreased in vivo basal protein synthesis (PS) in the nonstimulated muscle compared with time-matched Controls at 30 min, 4 h, and 12 h. In Control, but not EtOH, PS was decreased 15% after 30 min. In contrast, PS was increased in Control 4 h poststimulation but remained unchanged in EtOH. Last, stimulation increased PS 10% in Control and EtOH at 12 h, even though the absolute rate remained reduced by EtOH. The stimulation-induced increase in the phosphorylation of S6K1 Thr421/Ser424 (20–52%), S6K1 Thr389 (45–57%), and its substrate rpS6 Ser240/244 (37–72%) was blunted by EtOH at 30 min, 4 h, and 12 h. Phosphorylation of 4E-BP1 Ser65 was also attenuated by EtOH (61%) at 4 h. Conversely, phosphorylation of extracellular signal-regulated kinase Thr202/Tyr204 was increased by stimulation in Control and EtOH mice at 30 min but only in Control at 4 h. Our data indicate that acute EtOH intoxication suppresses muscle protein synthesis for at least 12 h and greatly impairs contraction-induced changes in synthesis and mTOR signaling.

scholarly journals The Regulation of Body and Skeletal Muscle Protein Metabolism by Hormones and Amino Acids

2006 ◽  
Vol 136 (1) ◽  
pp. 212S-217S ◽  
Author(s):  
Zhenqi Liu ◽  
Wen Long ◽  
David A. Fryburg ◽  
Eugene J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Metabolism

Nutritional Supplementation and Resistance Exercise: What Is the Evidence for Enhanced Skeletal Muscle Hypertrophy?

2000 ◽  
Vol 25 (6) ◽  
pp. 524-535 ◽  
Author(s):  
Martin J. Gibala
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Resistance Exercise ◽  
Muscle Fibre ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Creatine Supplementation ◽  
Nutritional Supplementation ◽  
Practical Recommendation ◽  
Single Bout

Many athletes and recreational weightlifters believe that dietary manipulations-either following a single bout of resistance exercise or during habitual training-may augment the normal gains in muscle fibre hypertrophy. Very few studies, however, have directly examined the effect of nutritional supplementation on muscle protein metabolism after resistance exercise. Ingestion of an amino acid and/or carbohydrate solution during the initial hours following a single bout of resistance exercise promotes an acute increase in protein net balance compared to the fasted state. The precise mechanism involved has not been elucidated but seems related to an increased availability of intracellular amino acids and/or an increase in plasma insulin concentration. As a practical recommendation, therefore, postexercise feeding appears to be very important. Recent evidence suggests that creatine supplementation in conjunction with resistance training may elicit larger increases in muscle fibre cross-sectional area compared to training alone. This intervention may be most beneficial in persons with "compromised" skeletal muscle. Key words: protein metabolism, amino acids, creatine, insulin, human

scholarly journals Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 286-294 ◽  
Author(s):  
Adel Amirouche ◽  
Anne-Cécile Durieux ◽  
Sébastien Banzet ◽  
Nathalie Koulmann ◽  
Régis Bonnefoy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Protein Metabolism ◽  
Skeletal Muscle Mass ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Gene Electrotransfer ◽  
Mtor Signaling Pathway

Myostatin, a member of the TGF-β family, has been identified as a master regulator of embryonic myogenesis and early postnatal skeletal muscle growth. However, cumulative evidence also suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression and that myostatin may contribute to muscle mass loss in adulthood. Two major branches of the Akt pathway are relevant for the regulation of skeletal muscle mass, the Akt/mammalian target of rapamycin (mTOR) pathway, which controls protein synthesis, and the Akt/forkhead box O (FOXO) pathway, which controls protein degradation. Here, we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt/mTOR signaling pathway. Electrotransfer of a myostatin expression vector into the tibialis anterior muscle of Sprague Dawley male rats increased myostatin protein level and decreased skeletal muscle mass 7 d after gene electrotransfer. Using RT-PCR and immunoblot analyses, we showed that myostatin overexpression was ineffective to alter the ubiquitin-proteasome pathway. By contrast, myostatin acted as a negative regulator of Akt/mTOR pathway. This was supported by data showing that the phosphorylation of Akt on Thr308, tuberous sclerosis complex 2 on Thr1462, ribosomal protein S6 on Ser235/236, and 4E-BP1 on Thr37/46 was attenuated 7 d after myostatin gene electrotransfer. The data support the conclusion that Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. Myostatin down-regulates Akt/mammalian target of rapamycin (mTOR) signaling pathway uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.

scholarly journals Biochemical approaches for nutritional support of skeletal muscle protein metabolism during sepsis

2004 ◽  
Vol 17 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Thomas C. Vary ◽  
Christopher J. Lynch
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Metabolic Response ◽  
Muscle Protein ◽  
The Body ◽  
Integrated Analysis ◽  
Skeletal Muscle Protein ◽  
Catabolic State ◽  
N Metabolism ◽  
Induced Defects

Sepsis initiates a unique series of modifications in the homeostasis of N metabolism and profoundly alters the integration of inter-organ cooperatively in the overall N and energy economy of the host. The net effect of these alterations is an overall N catabolic state, which seriously compromises recovery and is semi-refractory to treatment with current therapies. These alterations lead to a functional redistribution of N (amino acids and proteins) and substrate metabolism among injured tissues and major body organs. The redistribution of amino acids and proteins results in a quantitative reordering of the usual pathways of C and N flow within and among regions of the body with a resultant depletion of the required substrates and cofactors in important organs. The metabolic response to sepsis is a highly integrated, complex series of reactions. To understand the regulation of the response to sepsis, a comprehensive, integrated analysis of the fundamental physiological relationships of key metabolic pathways and mechanisms in sepsis is essential. The catabolism of skeletal muscles, which is manifested by an increase in protein degradation and a decrease in synthesis, persists despite state-of-the-art nutritional care. Much effort has focused on the modulation of the overall amount of nutrients given to septic patients in a hope to improve efficiencies in utilisation and N economies, rather than the support of specific end-organ targets. The present review examines current understanding of the processes affected by sepsis and testable means to circumvent the sepsis-induced defects in protein synthesis in skeletal muscle through increasing provision of amino acids (leucine, glutamine, or arginine) that in turn act as nutrient signals to regulate a number of cellular processes.

Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans

1991 ◽  
Vol 260 (3) ◽  
pp. E499-E504 ◽  
Author(s):  
D. A. Fryburg ◽  
R. A. Gelfand ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Igf I ◽  
Normal Humans

The short-term effects of growth hormone (GH) on skeletal muscle protein synthesis and degradation in normal humans are unknown. We studied seven postabsorptive healthy men (age 18-23 yr) who received GH (0.014 micrograms.kg-1.min-1) via intrabrachial artery infusion for 6 h. The effects of GH on forearm amino acid and glucose balances and on forearm amino acid kinetics [( 3H]Phe and [14C]Leu) were determined after 3 and 6 h of the GH infusion. Forearm deep vein GH rose to 35 +/- 6 ng/ml in response to GH, whereas systemic levels of GH, insulin, and insulin-like growth factor I (IGF-I) were unchanged. Forearm glucose uptake did not change during the study. After 6 h, GH suppressed forearm net release (3 vs. 6 h) of Phe (P less than 0.05), Leu (P less than 0.01), total branched-chain amino acids (P less than 0.025), and essential neutral amino acids (0.05 less than P less than 0.1). The effect on the net balance of Phe and Leu was due to an increase in the tissue uptake for Phe (71%, P less than 0.05) and Leu (37%, P less than 0.005) in the absence of any significant change in release of Phe or Leu from tissue. In the absence of any change in systemic GH, IGF-I, or insulin, these findings suggest that locally infused GH stimulates skeletal muscle protein synthesis. These findings have important physiological implications for both the role of daily GH pulses and the mechanisms through which GH can promote protein anabolism.

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