A Limited Role for PI(3,4,5)P3 Regulation in Controlling Skeletal Muscle Mass in Response to Resistance Exercise

Division of Molecular Physiology, University of Dundee, Dundee, Scotland, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 07/2010; 5(7):e11624. DOI: 10.1371/journal.pone.0011624
Source: PubMed


Since activation of the PI3K/(protein kinase B; PKB/akt) pathway has been shown to alter muscle mass and growth, the aim of this study was to determine whether resistance exercise increased insulin like growth factor (IGF) I/phosphoinositide 3-kinase (PI3K) signalling and whether altering PI(3,4,5)P(3) metabolism genetically would increase load induced muscle growth.
Acute and chronic resistance exercise in wild type and muscle specific PTEN knockout mice were used to address the role of PI(3,4,5)P(3) regulation in the development of skeletal muscle hypertrophy. Acute resistance exercise did not increase either IGF-1 receptor phosphorylation or IRS1/2 associated p85. Since insulin/IGF signalling to PI3K was unchanged, we next sought to determine whether inactivation of PTEN played a role in load-induced muscle growth. Muscle specific knockout of PTEN resulted in small but significant increases in heart (PTEN(+/+) = 5.00+/-0.02 mg/g, PTEN(-/-) = 5.50+/-0.09 mg/g), and TA (PTEN(+/+) = 1.74+/-0.04 mg/g, PTEN(-/-) = 1.89 +/-0.03) muscle mass, while the GTN, SOL, EDL and PLN remain unchanged. Following ablation, hypertrophy of the PLN, SOL or EDL muscles was similar between PTEN(-/-) and PTEN(+/+) animals. Even though there were some changes in overload-induced PKB and S6K1 phosphorylation, 1 hr following acute resistance exercise there was no difference in the phosphorylation state of S6K1 Thr389 between genotypes.
These data suggest that physiological loading does not lead to the enhanced activation of the PI3K/PKB/mTORC1 axis and that neither PI3K activation nor PTEN, and by extension PI(3,4,5)P(3) levels, play a significant role in adult skeletal muscle growth.

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    • "Rats underwent a bout of acute unilateral resistance exercise using a protocol described previously (Baar & Esser, 1999; Hamilton et al., 2010). Briefly, rats were anesthetized (2.5% isoflurane) and the sciatic nerve was stimulated (100 Hz, 3-6 volts, 1 ms pulse, 9 ms delay) using percutaneous wire electrodes to contract the hindlimb muscles for 10 sets of 6 repetitions (repetition length = 2 s). "
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    ABSTRACT: This study aimed to determine i) the effect of acute resistance exercise on mechanisms of ribosome biogenesis, and ii) the impact of mammalian target of rapamycin on ribosome biogenesis, and muscle protein synthesis (MPS) and degradation. Female F344BN rats underwent unilateral electrical stimulation of the sciatic nerve to mimic resistance exercise in the tibialis anterior (TA) muscle. TA muscles were collected at intervals over the 36 h of exercise recovery (REx); separate groups of animals were administered rapamycin pre-exercise (REx+Rapamycin). Resistance exercise led to a prolonged (6 to 36 h) elevation (30-50%) of MPS that was fully blocked by rapamycin at 6 hours but only partially at 18 h. REx also altered pathways that regulate protein homeostasis and mRNA translation in a manner that was both rapamycin-sensitive (proteasome activity; phosphorylation of S6K1 and rpS6) and insensitive (phosphorylation of eEF2, ERK1/2 and UBF; gene expression of the myostatin target Mighty as well as c-Myc and its targets involved in ribosome biogenesis). The role of c-Myc was tested in vitro using the inhibitor 10058-F4, which, over time, decreased basal RNA and MPS in a dose-dependent manner (correlation of RNA and MPS, r(2) = 0.98), even though it had no effect on the acute stimulation of protein synthesis. In conclusion, acute resistance exercise stimulated rapamycin-sensitive and -insensitive mechanisms that regulate translation activity and capacity. This article is protected by copyright. All rights reserved.
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    • "This places Rheb in a guanosine triphosphate (GTP) bound state where it can ultimately evoke mTORC1 activity (Sato et al. 2009). Interestingly, unlike insulin/growth factors , both amino acids (Smith et al. 2005) and mechanical loading (Hamilton et al. 2010) induce mTORC1-dependent signalling via pathways distinct of PI3K. Instead, amino acids and mechanical loading act through divergent pathways to converge on, and synergistically enhance, mTORC1 activation (Dreyer et al. 2008). "
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    ABSTRACT: Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may amplify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.
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    • "To induce EDL muscle overload, in a different set of animals, unilateral synergistic ablation of the tibialis anterior muscle was carried out as previously described (Rosenblatt and Parry 1992; Hamilton et al. 2010). The contralateral limb was submitted to sham surgery. "
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