Mammalian target of rapamycin (mTOR) is a central controller of cell growth. mTOR assembles into two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. Here we show that the mTORC1 component raptor is critical for muscle function and prolonged survival. In contrast, muscles lacking the mTORC2 component rictor are indistinguishable from wild-type controls. Raptor-deficient muscles become progressively dystrophic, are impaired in their oxidative capacity, and contain increased glycogen stores, but they express structural components indicative of oxidative muscle fibers. Biochemical analysis indicates that these changes are probably due to loss of activation of direct downstream targets of mTORC1, downregulation of genes involved in mitochondrial biogenesis, including PGC1alpha, and hyperactivation of PKB/Akt. Finally, we show that activation of PKB/Akt does not require mTORC2. Together, these results demonstrate that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.
Background-Cardiac hypertrophy involves growth responses to a variety of stimuli triggered by increased workload. It is an independent risk factor for heart failure and sudden death. Mammalian target of rapamycin (mTOR) plays a key role in cellular growth responses by integrating growth factor and energy status signals. It is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC) 1 and mTORC2. The role of each of these branches of mTOR signaling in the adult heart is currently unknown. Methods and Results-We generated mice with deficient myocardial mTORC1 activity by targeted ablation of raptor, which encodes an essential component of mTORC1, during adulthood. At 3 weeks after the deletion, atrial and brain natriuretic peptides and -myosin heavy chain were strongly induced, multiple genes involved in the regulation of energy metabolism were altered, but cardiac function was normal. Function deteriorated rapidly afterward, resulting in dilated cardiomyopathy and high mortality within 6 weeks. Aortic banding-induced pathological overload resulted in severe dilated cardiomyopathy already at 1 week without a prior phase of adaptive hypertrophy. The mechanism involved a lack of adaptive cardiomyocyte growth via blunted protein synthesis capacity, as supported by reduced phosphorylation of ribosomal S6 kinase 1 and 4E-binding protein 1. In addition, reduced mitochondrial content, a shift in metabolic substrate use, and increased apoptosis and autophagy were observed. Conclusions-Our results demonstrate an essential function for mTORC1 in the heart under physiological and pathological conditions and are relevant for the understanding of disease states in which the insulin/insulin-like growth factor signaling axis is affected such as diabetes mellitus and heart failure or after cancer therapy. (Circulation. 2011;123:1073-1082.)Key Words: heart failure Ⅲ hypertrophy Ⅲ myocardial metabolism Ⅲ signal transduction A lthough cardiac hypertrophy is a growth response that initially normalizes wall tension, it is associated with an unfavorable outcome: Affected patients are threatened with sudden death or progression to heart failure. 1 Much research is therefore aimed at understanding myocardial growth regulation, and in this setting, the insulin-like growth factor/PI3-kinase/Akt signaling cascade has been studied extensively. 2,3 Experiments with cultured cardiomyocytes have suggested that downstream of Akt, mammalian target of rapamycin (mTOR) mediates responses to pathological stimuli. 4,5 mTOR is an evolutionary conserved Ser/Thr kinase known to control cell growth. 6 Nutrient, energy, and growth factor shortage will impair mTOR activity, resulting in diverse effects, including the slowdown of macromolecule synthesis, enhanced autophagy, and activation of nutrient-or stressresponsive transcription factors. mTOR is found in 2 structurally and functionally distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. The 2 best-characterized substrates of mTORC1 ...
The renin-angiotensin system regulates normal cardiovascular homeostasis and is activated in certain forms of hypertension and in heart failure. Angiotensin II has multiple physiological effects and we have shown recently that its growth-promoting effects on vascular smooth muscle require autocrine activation of the IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk, respectively) and IGF binding protein-3 levels, and increased IGF binding protein-2 levels, a pattern suggestive of dietary restriction. Compared with sham, angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and pair-feeding experiments indicated that 74% of this loss was attributable to a reduction in food intake. The vasodilator hydralazine and the AT 1 receptor antagonist losartan had comparable effects to reverse angiotensin II-induced hypertension, but only losartan blocked the changes in body weight and in circulating IGF I and its binding proteins produced by angiotensin II. Moreover, in Dahl rats that were hypertensive in response to a high-salt diet, none of these changes occurred. Thus, angiotensin II produces weight loss through a pressor-independent mechanism that includes a marked anorexigenic effect and an additional (likely metabolic) effect. These findings have profound implications for understanding the pathophysiology of conditions, such as congestive heart failure, in which the renin-angiotensin system is activated. ( J. Clin. Invest. 1996. 97:2509-2516.)
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