Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

Vega, Rick B.; Konhilas, John P.; Kelly, Daniel P.; Leinwand, Leslie A.

doi:10.1016/j.cmet.2017.04.025

Cited by 230 publications

(175 citation statements)

References 161 publications

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“…The ExT‐induced upregulation of cardiac ACTA1 expression in aged mice was unexpected. ACTA1 is a member of the “fetal" gene profile typically increased in pathological cardiac hypertrophy and downregulated in exercise‐induced physiological hypertrophy (Vega, Konhilas, Kelly, & Leinwand, 2017). However, high‐intensity ExT can increase ACTA1 expression in the heart (Castro et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Roh

Houstis

et al. 2020

Aging Cell

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Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24–30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age‐related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF.

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Section: Discussionmentioning

confidence: 99%

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Roh

Houstis

et al. 2020

Aging Cell

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“…Persons that practice long-term moderate aerobic endurance training experi- ence an overall increase in aerobic capacity of muscles, and reduced resting blood pressure and heart rate. Gene expression alterations as a result of exercise are similar in skeletal and cardiac muscle, with an increase in fatty acid oxidation (metabolic pathways such as the insulin receptor/PI3K-Akt pathway), which in turn affect PGC1α and PPARα (AMPK signaling pathway) [45]. Improvement in lipid metabolism directly affects atherosclerosis progression, by minimizing circulating LDL available for potential uptake and storage within vessels [24].…”

Section: Discussionmentioning

confidence: 99%

“…In order to achieve maximum flow of oxygen and metabolites, muscle cells release factors into the blood that lead to systemic vasodilation [44,45]. Moreover, as mentioned above, skeletal muscle can release anti-inflammatory cytokines that can influence plaque development in the periphery [7,9].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE<sup>–/–</sup> and Wild-Type Mice

et al. 2018

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Background: Atherosclerosis is the leading cause of death worldwide. The disease development is by and large driven by old age and lifestyle factors, such as diet, physical activity, and smoking. In the present study, we have investigated the effect of exercise and diet on the development of atherosclerosis in young and aged mice. Objective: This study aimed at comparing multiple age-dependent factors that may influence atherosclerosis in a transgenic mouse model. Methods: Young (14 weeks) and aged (49–52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE^–/– mice were subjected to physical endurance exercise on a treadmill, with or without a high-fat diet. Five weeks later, the frequencies of regulatory T cells (T_REGs) in lymph nodes were assessed by flow cytometry, plasmatic cytokines (interleukin [IL]-1β, IL-6, IL-10, IL-17, interferon-γ, tumor necrosis factor-α, and transforming growth factor [TGF]-β₁) levels were determined by Luminex assay. Lipids (cholesterol and triglycerides) and anti-heat shock protein 60 (HSP60) autoantibodies were measured by ELISA. Aortic lesion sizes were assessed by en face imaging. Microarray analysis and qPCR of skeletal muscle gene expression were also performed. Results: Exercise leads to a reduction of aortic lesions in young ApoE^–/– and aged WT mice independent of diet. In most groups, this reduction was followed by an increased proportion of T_REGs and TGF-β₁ levels. Moreover, gene expression analysis showed that exercise seems to affect the AMPK signaling pathway. In particular, PGC-1α₁ mRNA was induced in aged WT mice, whereas it was reduced in young ApoE^–/– mice. In addition, GSEA analysis showed a marked reduction in the insulin signaling pathway in aged ApoE^–/– mice. Conclusion: Practicing endurance exercise seems to be enough for reducing early aortic lesion formation, independent of diet. However, this was only true in mice with smaller aortic lesions, since mice with large, advanced, complicated atherosclerotic plaques did not show any reduction in lesion size with exercise training.

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“…Exercise promotes cardiovascular wellness, 1 augments musculoskeletal function, 2 and lengthens lifespan. 3 These salutary effects of exercise are dependent on the ability of the body to adapt to recurrent bouts of physical activity.…”

Section: Introductionmentioning

confidence: 99%

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Gibb¹,

Epstein²,

et al. 2017

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Background Exercise promotes metabolic remodeling in the heart, which is associated with physiologic cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiologic cardiac growth. Methods We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. Results Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, upon exercise adaptation and recovery there was an increase in myocardial phosphofructokinase activity and glycolysis. Cardiac-specific expression of a kinase-deficient PFK2 transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient PFK2 in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiologic cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. Conclusions Exercise-induced decreases in glycolytic activity stimulate physiologic cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

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Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

Cited by 230 publications

References 161 publications

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE<sup>–/–</sup> and Wild-Type Mice

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

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