P.1282, 6-Dimethoxy-1, 4-benzoquinone increases skeletal muscle mass through Akt/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.

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Changes in muscle mass with mechanical load: possible cellular mechanismsThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-010 ◽

2009 ◽

Vol 34 (3) ◽

pp. 328-335 ◽

Cited By ~ 38

Author(s):

Espen E. Spangenburg

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Muscle Mass ◽

Mechanical Load ◽

Peer Review Process ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Signaling Mechanism ◽

Selection Of

Understanding the mechanisms that regulate skeletal muscle mass has remained a focus of numerous researchers for many years. Recent investigations have begun to elucidate cellular signaling mechanisms that regulate skeletal muscle hypertrophy, with significant effort being focused on the Akt/mammalian target of rapamycin (mTOR) signaling pathway. The Akt/mTOR pathway plays a major role in regulating the initiation of protein synthesis after the onset of mechanical loading of skeletal muscle. Although a number of downstream substrates for Akt/mTOR have been elucidated, very little is known about the upstream mechanisms that mechanical load employs to activate the Akt/mTOR signaling pathway. Thus, the purpose of this review is to discuss potential mechanisms that may contribute to the activation of the Akt/mTOR signaling mechanism in mechanically loaded skeletal muscle.

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Ovariectomy prevents the recovery of atrophied gastrocnemius skeletal muscle mass

Journal of Applied Physiology ◽

10.1152/japplphysiol.00869.2005 ◽

2006 ◽

Vol 100 (1) ◽

pp. 286-293 ◽

Cited By ~ 69

Author(s):

Mitchell Sitnick ◽

Andrea M. Foley ◽

Marybeth Brown ◽

Espen E. Spangenburg

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Muscle Mass ◽

Recovery Period ◽

Mtor Signaling ◽

Hindlimb Unloading ◽

Medial Gastrocnemius ◽

Surgical Removal ◽

Mtor Signaling Pathway ◽

Ovx Rats

The recovery of atrophied muscle mass in animals is thought to be dependent on a number of factors including hormones, cytokines, and/or growth factor expression. The Akt/mammalian target of rapamycin (mTOR) signaling pathway is believed to be activated by these various factors, resulting in skeletal muscle growth through the initiation of protein synthesis. It was hypothesized that surgical removal of the ovaries (Ovx) may alter activation of the Akt/mTOR signaling pathway, a mechanism necessary for muscle regrowth. To test this, 36 Sprague-Dawley rats underwent Ovx or sham surgeries. A portion of the animals were then subjected to hindlimb unloading (HLU) for 28 days. After HLU, one group of Sham and Ovx rats underwent a 14-day recovery period in which the animals were allowed free cage ambulation. The HLU animals demonstrated ∼21–27% reduction in medial gastrocnemius muscle mass irrespective of whether the ovaries were intact or not. The Sham animals that were reloaded recovered their atrophied muscle mass; however, the Ovx group failed to recover any of the atrophied muscle mass with reloading. The failure to recover muscle mass in the Ovx group was associated with reduced phosphorylation levels of both Akt and p70s6k, whereas in the Sham recovery animals no reductions were found in Akt phosphorylation and significant increases in p70s6k activation were detected. Finally, no differences were detected in mTOR phosphorylation in any of Sham or Ovx groups. These results suggest that ovariectomy surgeries could be detrimental to the recovery of atrophied muscle mass.

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Effect of Supplemental Dietary Zinc on the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Skeletal Muscle and Liver from Post-absorptive Mice

Biological Trace Element Research ◽

10.1007/s12011-007-0018-8 ◽

2007 ◽

Vol 118 (1) ◽

pp. 65-76 ◽

Cited By ~ 22

Author(s):

James P. McClung ◽

Tyson N. Tarr ◽

Brian R. Barnes ◽

Angus G. Scrimgeour ◽

Andrew J. Young

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mtor Signaling Pathway ◽

Dietary Zinc

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Effects of aerobic exercise training on the protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway in aged skeletal muscle

Experimental Gerontology ◽

10.1016/j.exger.2003.12.005 ◽

2004 ◽

Vol 39 (3) ◽

pp. 379-385 ◽

Cited By ~ 13

Author(s):

Thomas H Reynolds ◽

Pamela Reid ◽

Lisa M Larkin ◽

Donald R Dengel

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Exercise Training ◽

Aerobic Exercise ◽

Signaling Pathway ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Aerobic Exercise Training ◽

Mtor Signaling Pathway

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Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00068.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. E873-E881 ◽

Cited By ~ 16

Author(s):

Yu Chen ◽

Sumita Sood ◽

Kevin McIntire ◽

Richard Roth ◽

Ralph Rabkin

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Signaling Pathway ◽

Muscle Wasting ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Exercise Induced ◽

Rps6 Phosphorylation

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

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