Article, see p 2144
In 1942, Rudolf Schoenheimer 1 introduced the concept of The Dynamic State of Body Constituents . Schoenheimer was the first to use stable isotopes as labels in organic compounds destined for experiments in the mammalian body. From his results, he concluded that, “not only the fuel, but also the structural materials, are in a steady state of flux.” 1 Today this concept is more relevant than ever.
Along with well-documented changes in skeletal muscle, an important component of the mammalian response to exercise training is dynamic cardiac remodeling required to adapt cardiac output to peripheral demand. The process of physiological cardiac hypertrophy shares some mechanisms with the pathological hypertrophy seen in heart failure or the response to myocardial infarction. The latter process has been intensely studied, with several molecular signaling mechanisms elucidated (eg, the calcineurin nuclear factor of activated T cell signaling axis). However, less is known about the molecular mechanisms underlying cardiac plasticity under a range of normal physiological situations including exercise. 경산출장연애인급
Cardiac function is metabolically demanding, and although the heart is typically thought of as a metabolic omnivore, under steady-state conditions, the bulk of myocardial ATP requirements are met by mitochondrial β-oxidation of fatty acids. 평택출장샵콜걸 The pathways of cardiac metabolism remodel extensively in response to interventions both pathological (heart failure) and physiological (exercise training). 4 , 군산출장외국인 A key question remains: Is cardiac metabolic remodeling merely a responsive epiphenomenon that accompanies structural hypertrophy or can it play a causative role in driving hypertrophy?
In the case of pathological hypertrophy, mitochondrial DNA mutations are known to cause cardiomyopathy, 6 and several mouse models of altered metabolism exhibit either pathological cardiac hypertrophy at baseline or a worsening or amelioration of the response to hypertrophic stimuli such as pressure overload. 통영출장샵예약 , 구리출장업소 However, the role of metabolism as a governing factor in physiological hypertrophy is less well understood. A new article by Gibb et al 남원출장업소 in this issue of Circulation sheds some new light on this question: by using mice with cardiac-specific up- or downregulation of glycolysis, the authors demonstrate that manipulation of glycolysis alone is capable of inducing cardiac structural, metabolic, and functional alterations that mimic the effects of exercise training.
Although acute bouts of exercise induced a PKF2-linked depression in cardiac glycolytic flux (a phenomenon the authors attribute to acute changes in plasma substrate availability), 4 weeks of exercise caused a sustained PFK2-linked increase in cardiac glycolytic flux. Thus, similar to pathological hypertrophy, glycolysis and physiological hypertrophy are positively correlated. However, steady-state metabolomics yielded surprising findings: of 424 metabolites measured, levels of only 20 were significantly altered in trained versus sedentary hearts, and this list did not include any constituents of glycolysis. Furthermore, glycolytic enzyme levels were not altered by exercise. These results highlight the critical importance of flux measurements in metabolic studies. 보령오피걸 Metabolite or enzyme levels alone do not provide adequate information on pathway fluxes, for which it is often necessary to assess enzyme activities (ie, to deploy classical biochemical assays).
The authors next characterized the cardiac metabolomes of Glyco HI/LO mice, finding some expected changes: Glyco HI mice burned more glucose and less fat and vice versa for Glyco LO mice. Recognizing the potential metabolic parallels between exercised and Glyco HI/LO hearts, they next asked whether the hypertrophy seen in Glyco HI/LO was physiological (exercise-like) in nature. Although both Glyco LO/HI hearts exhibited cardiomyocyte enlargement, only Glyco LO hearts also enhanced capillary density. The profile of key signaling mediators seen in exercised hearts ( Cebpb , Cited4 , Nfat2c ) was also present in Glyco LO but not in Glyco HI hearts. The Figure shows the degree of overlap among metabolic, signaling, structural, and functional aspects of hypertrophy in the 3 models (exercise, Glyco LO , Glyco HI ). Although each model has unique features, the exercise phenotype overlaps more with Glyco LO than Glyco HI . The overall conclusion that Glyco LO hypertrophy is exercise-like is rather counterintuitive given the documented elevation in glycolysis that accompanies exercise training. 고양출장샵
To examine potential overlapping mechanisms between exercise- and Glyco LO -driven hypertrophy, the authors placed Glyco LO mice on an exercise regime. It is interesting to note that no further hypertrophy occurred, and exercised Glyco LO mice exhibited the same cardiac work and distance running capacities as exercised WT controls. These data suggest that the Glyco LO heart is already maximally adapted and cannot engage a further hypertrophic response. An important caution regarding the apparent preexercised phenotype of sedentary Glyco LO hearts is that mitochondrial defects (impaired respiration and ultrastructural abnormalities) were seen in both Glyco LO/HI hearts, and exercise did not correct these problems. This finding indicates that metabolic inflexibility is problematic in other ways, and inhibiting glycolysis alone is not a substitute for the beneficial cardiac effects of exercise.
A caveat to these studies is the degree of metabolic overlap between the models; 25% of all measured metabolites were different in either Glyco LO /WT or Glyco HI /WT. In addition, of 33 metabolites altered in both models, 22 were reciprocally altered between genotypes (ie, opposite effect in Glyco LO /WT versus Glyco HI /WT). Unfortunately, although these data indicate consistency between the 2 genetic models, the magnitude of such changes questions their suitability to study the more subtle metabolic alterations of exercise. To wit, only 5 of the 20 metabolites altered in exercise were also altered in Glyco LO /WT or Glyco HI /WT, suggesting that metabolic changes induced by PFK2 manipulation are fundamentally different in character than those induced by exercise training.
The manner in which metabolism may signal to bring about cardiac structural or functional changes seen in hypertrophy remains poorly understood. Many mitochondrial and cellular metabolites can function as signaling molecules (eg, by regulating protein post-translational modifications [PTMs]). The following are examples of how metabolites may bring about hypertrophic signaling events or gene expression patterns:
This work was support by the National Institutes of Health grants R01-HL071158 (PSB) and R01-HL061483 (HT).