Loaded wheel running and muscle adaptation in the mouse

Konhilas, John P.; Widegren, Ulrika; Allen, David L.; Paul, Angelika C.; Cleary, Allison S.; Leinwand, Leslie A.

doi:10.1152/ajpheart.00085.2005

Cited by 94 publications

(139 citation statements)

References 60 publications

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“…As shown in Table 2, Exmice had less visceral adipose tissue and a lower liver weight, consistent with results reported for rats using a running wheel for a shorter period [17]. The weight of the soleus muscle increased after long-term exercise (Table 2), which is in agreement with previous findings [31,32]. Qualitative muscular change was also examined in this model [31,32].…”

Section: Discussionsupporting

confidence: 90%

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Long-term voluntary exercise, representing habitual exercise, lowers visceral fat and alters plasma amino acid levels in mice

Takeshita

Horiuchi

Izumo

et al. 2011

Environ Health Prev Med

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Objectives To determine the impact of long-term voluntary exercise, representing habitual exercise for the prevention of lifestyle-related diseases, on glucose, lipid, and amino acid metabolism in mice. Methods Twenty-four mice aged 6 weeks were divided into three groups. Two groups (16 mice) were housed individually in either cages equipped with a running wheel (8 mice, exercising, Ex-mice) or without (8 mice, sedentary, Se-mice) for 24 weeks. The remaining group (8 mice) was sacrificed at 6 weeks of age. Biomarkers related to glucose, lipid, and amino acid metabolism were examined.Results Ex-mice ran voluntarily, predominantly in the dark. The distance per day peaked at 4 weeks and then decreased until 12 weeks to around the level seen at the beginning of the experimental period, and was maintained at 4.9 ± 0.2 km/day from 12 to 24 weeks. Ex-mice showed a similar adrenal weight and vitamin C content to Se-mice but had a significantly lower body weight and higher food intake. Ex-mice also showed a higher skeletal muscle weight, a lower white adipose tissue and liver weight, associated with lower plasma leptin and insulin-like growth factor-1 levels, and a lower hepatic triglyceride content. Analysis of plasma amino acids showed that Ex-mice had significantly higher phenylalanine, tyrosine, and glutamine levels, resulting in a significantly lower Fischer's ratio. Conclusions We present an animal model of long-term voluntary exercise under low stress. Findings related to the effects of long-term voluntary exercise on lipid, and amino acid metabolism in our mouse model indicate that such an exercise regimen may affect pathophysiological states related to appetite and behavior.

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Section: Discussionsupporting

confidence: 90%

“…The weight of the soleus muscle increased after long-term exercise (Table 2), which is in agreement with previous findings [31,32]. Qualitative muscular change was also examined in this model [31,32]. Hepatic TG content, but not cholesterol, was significantly reduced in Ex-mice compared to Se-mice (Table 2).…”

Section: Discussionsupporting

confidence: 90%

Long-term voluntary exercise, representing habitual exercise, lowers visceral fat and alters plasma amino acid levels in mice

Takeshita

Horiuchi

Izumo

et al. 2011

Environ Health Prev Med

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“…All animal experiments were approved by the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill. Physiologic hypertrophy was induced by unloaded voluntary wheel running in female mice as previously described (32). Briefly, Atrogin-1 -/-mice were assigned to either no-resistance wheel running (n = 6) or sedentary control (n = 3).…”

Section: Methodsmentioning

confidence: 99%

Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins

Li¹,

Willis²,

Lockyer³

et al. 2007

J. Clin. Invest.

231

230

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Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63-linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors. IntroductionFactors that increase LV afterload - such as hypertension, aortic stenosis, and age-related arterial stiffness - elicit cardiac hypertrophy as an adaptive mechanism to normalize wall stress. The shortterm hemodynamic benefits of hypertrophy occur at a cost: cardiac hypertrophy leads to diastolic dysfunction and heart failure and is a powerful predictor of cardiovascular mortality even in the absence of symptoms (1, 2). At the cellular level, cardiac hypertrophy is a consequence of increased cardiomyocyte cell volume (1, 2), a process that requires coordination of cellular signaling cascades, activation of fetal cardiac gene expression programs, increased protein synthesis, sarcomere assembly, and modulation of cellular energy sources. At the present time, no specific pharmacologic strategies to reverse cardiac hypertrophy have been approved for clinical use, so the delineation of hypertrophic mechanisms (especially those that prevent or reverse hypertrophy) remains a priority.Although complexity and redundancy exist in the signaling pathways that activate cardiac hypertrophy, 2 independent circuits that elicit distinct manifestations of hypertrophy are now recognized. Hypertrophy in response to stimuli such as pressure overload and adrenergic stimulation activates the calcineurin/ nuclear factor of activated T cell-dependent signaling pathway, resulting in so-called "pathological" hypertrophy that is associated with maladaptive features such as fibrosis, chamber dilatation,

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“…However, these genes display a considerable degree of functional overlap, as combined deletion of Akt1 and Akt2 genes results in perinatal lethality with severe growth retardation and multiple developmental defects (18). In the heart, Akt is an important positive regulator of normal postnatal cardiac growth (19) and is also activated by exercise training (20)(21)(22), by pressure overload (23), and in diseased human hearts (24). In addition, overexpression of activated Akt1 or Akt3 in the heart under the control of α-myosin heavy chain (α-MHC) promoter is sufficient to induce cardiac hypertrophy and, in some cases, contractile dysfunction in Tg mice (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure

Shiojima

Sato

Izumiya

et al. 2005

Journal of Clinical Investigation

846

739

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Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.

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Loaded wheel running and muscle adaptation in the mouse

Cited by 94 publications

References 60 publications

Long-term voluntary exercise, representing habitual exercise, lowers visceral fat and alters plasma amino acid levels in mice

Long-term voluntary exercise, representing habitual exercise, lowers visceral fat and alters plasma amino acid levels in mice

Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins

Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure

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