MRS-based metabolic profiling of cardiac and skeletal muscle from rats with heart failure, low intrinsic fitness, aging and exercise training

Abstract

Background: Heart failure is associated with reduced exercise capacity and impaired myocardial and skeletal muscle metabolism. Other factors, such as inborn genetic difference, aging, and exercise training, can also lead to different exercise capacity. The purpose of this thesis was to use magnetic resonance spectroscopy (MRS) to determine metabolic profiles in myocardial and skeletal muscle, associated with heart failure and exercise capacity, and thus identify targets for clinical MRS in vivo. Methods: Two experimental models in rats were used in this thesis. Coronary artery ligation was applied to induce heart failure, and low versus high capacity runners (LCR/HCR) were used to mimic individuals with different intrinsic exercise capacity. LCR/HCR rats were divided into 9 and 18 months groups to investigate the effect of aging. In heart failure, exercise training was performed at moderate and high intensity. In LCR/HCR training intensity was high, whereas frequency was reduced. Magnetic resonance spectra were acquired from myocardial or skeletal muscle extracts. A combination of univariate (t-test and analysis of variance) and multivariate methods (principal component analysis or partial least square discriminative analysis) were used to determine the differences in metabolic profile. Results: Heart failure affected multiple metabolic pathways, including creatine metabolism, glucose metabolism, glutamine metabolism, and aspartate metabolism, whereas it had a limited effect on skeletal muscle metabolism. Exercise training increased adenosine triphosphate and decreased glucose in the myocardium. In addition, it altered the skeletal muscle metabolism by regulating the metabolism of taurine, hypotaurine, and carnitine. In the LCR/HCR model, high intrinsic fitness was associated with higher glutamine and glutamate, as well as lower lactate levels in skeletal muscle. Aging was associated with increased glycerophosphocholine and glucose levels. Exercise training did not cause any detectable changes on metabolic profile in LCR/HCR. Conclusion: MRS spectroscopy identified several myocardial and skeletal muscle metabolic profiles associated with the characteristic changes in cardiac function and aerobic fitness in heart failure, exercise training, aging and intrinsic running capacity. Although some of them pointed to pathways of putative mechanistic importance, further research is necessary to determine their potential as diagnostic and prognostic biomarkers.