Links between Exercise Capacity, Exercise Training, and Metabolism.

Exercise capacity of an individual describes the ability to perform physical activity. This exercise capacity is influenced by intrinsic factors such as genetic constitution and extrinsic factors such as exercise training. On the metabolic level exercise and metabolism are linked. As an important site of metabolism and the main source for ATP needed for muscle contraction, mitochondrial function can determine exercise capacity, and exercise inversely influences mitochondrial function. It has been suggested that exercise mediates many of its effects due to such metabolic changes. Although extrinsic factors affect exercise capacity, a major part of an individual's exercise capacity is genetically determined, and extrinsic factors can only improve on this baseline. Looking at the effect of exercise capacity on and with disease, the two go hand in hand. On one hand, disease is negatively affecting an individual's exercise capacity; on the other hand, exercise offers an effective treatment option. Combining these factors, exercise capacity is an often-ignored prognostic variable for life expectancy as well as morbidity and mortality. In this review, we aim to provide the current knowledge on the links between inherited and acquired exercise capacity, as well as the mechanisms in which metabolism interacts with exercise capacity. © 2023 American Physiological Society. Compr Physiol 13:5115-5155, 2023.

Targeting Mitochondrial Metabolism to Save the Failing Heart.

Despite considerable progress in treating cardiac disorders, the prevalence of heart failure (HF) keeps growing, making it a global medical and economic burden. HF is characterized by profound metabolic remodeling, which mostly occurs in the mitochondria. Although it is well established that the failing heart is energy-deficient, the role of mitochondria in the pathophysiology of HF extends beyond the energetic aspects. Changes in substrate oxidation, tricarboxylic acid cycle and the respiratory chain have emerged as key players in regulating myocardial energy homeostasis, Ca2+ handling, oxidative stress and inflammation. This work aims to highlight metabolic alterations in the mitochondria and their far-reaching effects on the pathophysiology of HF. Based on this knowledge, we will also discuss potential metabolic approaches to improve cardiac function.

Knockout of the Complex III subunit Uqcrh causes bioenergetic impairment and cardiac contractile dysfunction.

Ubiquinol cytochrome c reductase hinge protein (UQCRH) is required for the electron transfer between cytochrome c1 and c of the mitochondrial cytochrome bc1 Complex (CIII). A two-exon deletion in the human UQCRH gene has recently been identified as the cause for a rare familial mitochondrial disorder. Deletion of the corresponding gene in the mouse (Uqcrh-KO) resulted in striking biochemical and clinical similarities including impairment of CIII, failure to thrive, elevated blood glucose levels, and early death. Here, we set out to test how global ablation of the murine Uqcrh affects cardiac morphology and contractility, and bioenergetics. Hearts from Uqcrh-KO mutant mice appeared macroscopically considerably smaller compared to wildtype littermate controls despite similar geometries as confirmed by transthoracic echocardiography (TTE). Relating TTE-assessed heart to body mass revealed the development of subtle cardiac enlargement, but histopathological analysis showed no excess collagen deposition. Nonetheless, Uqcrh-KO hearts developed pronounced contractile dysfunction. To assess mitochondrial functions, we used the high-resolution respirometer NextGen-O2k allowing measurement of mitochondrial respiratory capacity through the electron transfer system (ETS) simultaneously with the redox state of ETS-reactive coenzyme Q (Q), or production of reactive oxygen species (ROS). Compared to wildtype littermate controls, we found decreased mitochondrial respiratory capacity and more reduced Q in Uqcrh-KO, indicative for an impaired ETS. Yet, mitochondrial ROS production was not generally increased. Taken together, our data suggest that Uqcrh-KO leads to cardiac contractile dysfunction at 9 weeks of age, which is associated with impaired bioenergetics but not with mitochondrial ROS production. Global ablation of the Uqcrh gene results in functional impairment of CIII associated with metabolic dysfunction and postnatal developmental arrest immediately after weaning from the mother. Uqcrh-KO mice show dramatically elevated blood glucose levels and decreased ability of isolated cardiac mitochondria to consume oxygen (O2). Impaired development (failure to thrive) after weaning manifests as a deficiency in the gain of body mass and growth of internal organ including the heart. The relative heart mass seemingly increases when organ mass calculated from transthoracic echocardiography (TTE) is normalized to body mass. Notably, the heart shows no signs of collagen deposition, yet does develop a contractile dysfunction reflected by a decrease in ejection fraction and fractional shortening.

The IGF-1R Inhibitor NVP-AEW541 Causes Insulin-Independent and Reversible Cardiac Contractile Dysfunction.

The antitumor treatment NVP-AEW541 blocks IGF-1R. IGF-1R signaling is crucial for cardiac function, but the cardiac effects of NVP-AEW541 are ill defined. We assessed NVP-AEW541's effects on cardiac function and insulin response in vivo and in isolated working hearts. We performed a dose-response analysis of NVP-AEW541 in male, 3-week-old rats and assessed the chronic effects of the clinically relevant dose in adult rats. We performed glucose tolerance tests and echocardiography; assessed the expression and phosphorylation of InsR/IGF-1R and Akt in vivo; and measured substrate oxidation, contractile function, and insulin response in the isolated working hearts. NVP-AEW541 caused dose-dependent growth retardation and impaired glucose tolerance in the juvenile rats. In the adults, NVP-AEW541 caused a continuously worsening depression of cardiac contractility, which recovered within 2 weeks after cessation. Cardiac Akt protein and phosphorylation were unchanged and associated with InsR upregulation. An acute application of NVP-AEW541 in the working hearts did not affect cardiac power but eliminated insulin's effects on glucose and fatty acid oxidation. The systemic administration of NVP-AEW541 caused dose- and time-dependent impairment of glucose tolerance, growth, and cardiac function. Because cardiac insulin signaling was maintained in vivo but absent in vitro and because contractile function was not affected in vitro, a direct link between insulin resistance and contractile dysfunction appears unlikely.

Targeting the alternative oxidase (AOX) for human health and food security, a pharmaceutical and agrochemical target or a rescue mechanism?

Some of the most threatening human diseases are due to a blockage of the mitochondrial electron transport chain (ETC). In a variety of plants, fungi, and prokaryotes, there is a naturally evolved mechanism for such threats to viability, namely a bypassing of the blocked portion of the ETC by alternative enzymes of the respiratory chain. One such enzyme is the alternative oxidase (AOX). When AOX is expressed, it enables its host to survive life-threatening conditions or, as in parasites, to evade host defenses. In vertebrates, this mechanism has been lost during evolution. However, we and others have shown that transfer of AOX into the genome of the fruit fly and mouse results in a catalytically engaged AOX. This implies that not only is the AOX a promising target for combating human or agricultural pathogens but also a novel approach to elucidate disease mechanisms or, in several cases, potentially a therapeutic cure for human diseases. In this review, we highlight the varying functions of AOX in their natural hosts and upon xenotopic expression, and discuss the resulting need to develop species-specific AOX inhibitors.

Genetically determined exercise capacity affects systemic glucose response to insulin in rats.

Aerobic exercise capacity is inversely related to morbidity and mortality as well as to insulin resistance. However, exercising in patients has led to conflicting results, presumably because aerobic exercise capacity consists of intrinsic (genetically determined) and extrinsic (environmentally determined) parts. The contribution of both parts to insulin sensitivity is also not clear. We investigated sedentary and exercised (aerobic interval training) high-capacity runners (HCR) and low-capacity runners (LCR) differing in their genetically determined aerobic exercise capacity to determine the contribution of both parts to insulin sensitivity. LCR and HCR differed in their untrained exercise capacity and body weight. Sedentary LCR displayed a diabetic phenotype with higher random glucose, lower glucose infusion rate during hyperinsulinemic euglycemic clamping than HCR. Echocardiography showed equal morphological and functional parameters and no change with exercise. Four week of exercise caused significant improvements in aerobic exercise capacity, which was more pronounced in LCR. However, with respect to glucose use, exercise affected HCR only. In these animals, exercise increased 2-deoxyglucose uptake in gastrocnemius (+58.5%, P = 0.1) and in epididymal fat (+106%; P < 0.05). Citrate synthase activity also increased in these tissues (gastrocnemius 69% epididymal fat 63%). In our model of HCR and LCR, genetic predisposition for low exercise capacity is associated with impaired insulin sensitivity and impedes exercise-induced improvements in insulin response. Our results suggest that genetic predisposition for low aerobic exercise capacity impairs insulin response, which may not be overcome by exercise.

High-fat diet affects skeletal muscle mitochondria comparable to pressure overload-induced heart failure.

In heart failure, high-fat diet (HFD) may exert beneficial effects on cardiac mitochondria and contractility. Skeletal muscle mitochondrial dysfunction in heart failure is associated with myopathy. However, it is not clear if HFD affects skeletal muscle mitochondria in heart failure as well. To induce heart failure, we used pressure overload (PO) in rats fed normal chow or HFD. Interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) from gastrocnemius were isolated and functionally characterized. With PO heart failure, maximal respiratory capacity was impaired in IFM but increased in SSM of gastrocnemius. Unexpectedly, HFD affected mitochondria comparably to PO. In combination, PO and HFD showed additive effects on mitochondrial subpopulations which were reflected by isolated complex activities. While PO impaired diastolic as well as systolic cardiac function and increased glucose tolerance, HFD did not affect cardiac function but decreased glucose tolerance. We conclude that HFD and PO heart failure have comparable effects leading to more severe impairment of IFM. Glucose tolerance seems not causally related to skeletal muscle mitochondrial dysfunction. The additive effects of HFD and PO may suggest accelerated skeletal muscle mitochondrial dysfunction when heart failure is accompanied with a diet containing high fat.

GLP-1 Improves Diastolic Function and Survival in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) has emerged as a public health burden with currently no effective medication. We assessed the treatment effects of the incretin hormone glucagon-like peptide-1 (GLP-1) on cardiac metabolism and function in a model of HFpEF. Following aortic banding, rats developed HFpEF characterized by diastolic dysfunction, pulmonary congestion, and poor survival (38%). A 4-week GLP-1 treatment via osmotic pumps significantly improved survival (70%) and reduced left ventricular stiffness, diastolic dysfunction, and pulmonary congestion. Isolated heart perfusion revealed preserved cardiac glucose oxidation (GO) and a shift in cardiac substrate utilization towards GO. While GLP-1 may boost insulin secretion and responsiveness, the protective effects were not related to cardiac insulin action. GLP-1 improves diastolic function and survival in rats with HFpEF, which was associated with a cardiac substrate switch towards GO. The therapeutic role of GLP-1 in HFpEF is new and warrants further investigation.