The Role of Exercise in Cardiac Aging

Roh, Jason D.; Rhee, James; Chaudhari, Vinita; Rosenzweig, Anthony

doi:10.1161/circresaha.115.305250

Cited by 118 publications

(94 citation statements)

References 241 publications

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“…In this case, as with myocardial growth during development, myocytes grow in diameter more than in length, a process that is called concentric hypertrophy(van Berlo et al 2013). Myocardial growth during exercise and pregnancy is reversible and does not lead to a pathological growth of the myocardium(Wasfy and Weiner 2015; Roh et al 2016). Finally, while it is not well studied, the increased myocyte size during exercise and pregnancy is associated with increased protein synthesis(Catalucci et al 2008; Li et al 2012; Chung and Leinwand 2014) and thus would be expected to increase the demands on protein folding machinery in the ER, as well as in the cytosol; however, it is evident that the UPR in the adult heart is sufficient to meet the demands of increased protein synthesis, because under these conditions, there does not appear to be any myocyte death.…”

Section: Physiological Conditions That Challenge the Er-pqc In Cardmentioning

confidence: 99%

ER Protein Quality Control and the Unfolded Protein Response in the Heart

Arrieta

Blackwood

Glembotski

2017

Current Topics in Microbiology and Immunology

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Cardiac myocytes are the cells responsible for the robust ability of the heart to pump blood throughout the circulatory system. Cardiac myocytes grow in response to a variety of physiological and pathological conditions; this growth challenges endoplasmic reticulum-protein quality control (ER-PQC), a major feature of which includes the unfolded protein response (UPR). ER-PQC and the UPR in cardiac myocytes growing under physiological conditions, including normal development, exercise, and pregnancy, are sufficient to support hypertrophic growth of each cardiac myocyte. However, the ER-PQC and UPR are insufficient to respond to the challenge of cardiac myocyte growth under pathological conditions, including myocardial infarction and heart failure. In part, this insufficiency is due to a continual decline in the expression levels of important adaptive UPR components as a function of age and during myocardial pathology. This chapter will discuss the physiological and pathological conditions unique to the heart that involves ER-PQC, and whether the UPR is adaptive or maladaptive under these circumstances.

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Section: Physiological Conditions That Challenge the Er-pqc In Cardmentioning

confidence: 99%

ER Protein Quality Control and the Unfolded Protein Response in the Heart

Arrieta

Blackwood

Glembotski

2017

Current Topics in Microbiology and Immunology

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“…5 Cardiovascular adaptations to exercise are particularly critical to enable adequate oxygen and nutrient delivery to peripheral tissues, and they help preserve circulatory system health with age. 6, 7 Physiological cardiac growth due to exercise is a key component of these cardiovascular adaptations and contributes not only to exercise capacity, but protects the heart from injury as well. 8 Nevertheless, the mechanisms by which regular exercise triggers and sustains cardiac adaptation remain unclear.…”

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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“…Moreover, these assessments are typically conducted in anesthetized animals further confounding the interpretation of hemodynamic and functional results. When combined with cardiac imaging or hemodynamic monitoring, exercise testing can provide tremendous insights into an animal’s physiologic reserves 8, 9 . Indeed, measuring exercise capacity integrates functional assessment of many of the previously mentioned HFpEF phenotypes, and is closely related to dyspnea on exertion, the cardinal HFpEF symptom.…”

Section: Viewpointmentioning

confidence: 99%

Why Don’t We Have Proven Treatments for HFpEF?

Roh

Houstis

Rosenzweig

2017

Circulation Research

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Summary The lack of effective treatments for heart failure with preserved ejection fraction (HFpEF) represents a large and growing unmet need in cardiology today. A critical obstacle to therapeutic innovation in HFpEF has been the absence of animal models that accurately recapitulate the complexities of the human disease. Here we propose that more comprehensive multi-organ system and functional phenotyping of preclinical models is essential if we are to maximize our chances of discovering and validating novel targets for effective therapeutic development in HFpEF.

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The Role of Exercise in Cardiac Aging

Cited by 118 publications

References 241 publications

ER Protein Quality Control and the Unfolded Protein Response in the Heart

ER Protein Quality Control and the Unfolded Protein Response in the Heart

Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth

Why Don’t We Have Proven Treatments for HFpEF?

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