Understanding Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current Knowledge and Emerging Concepts

Abstract

The benefits of exercise on the heart are well recognized, and clinical studies have demonstrated that exercise is an intervention that can improve cardiac function in heart failure patients. This has led to significant research into understanding the key mechanisms responsible for exercise-induced cardiac protection. Here, we summarize molecular mechanisms that regulate exercise-induced cardiac myocyte growth and proliferation. We discuss in detail the effects of exercise on other cardiac cells, organelles, and systems that have received less or little attention and require further investigation. This includes cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival (heat shock response, ubiquitin-proteasome system, autophagy-lysosomal system, endoplasmic reticulum unfolded protein response, DNA damage response), extracellular matrix, inflammatory response, and organ-to-organ crosstalk. We summarize therapeutic strategies targeting known regulators of exercise-induced protection and the challenges translating findings from bench to bedside. We conclude that technological advancements that allow for in-depth profiling of the genome, transcriptome, proteome and metabolome, combined with animal and human studies, provide new opportunities for comprehensively defining the signaling and regulatory aspects of cell/organelle functions that underpin the protective properties of exercise. This is likely to lead to the identification of novel biomarkers and therapeutic targets for heart disease.

Downregulation of miR-26b-5p, miR-204-5p, and miR-497-3p Expression Facilitates Exercise-Induced Physiological Cardiac Hypertrophy by Augmenting Autophagy in Rats

“…The difference is that physiological LVH is induced by aerobic exercise training, postnatal growth, and pregnancy, and characterized by unchanged fetal and apoptosis gene expression and increased cardiac function while pathological LVH is stimulated by pressure or volume overload or cardiomyopathy, and characterized by apoptosis and fibrosis and depressed cardiac function (Bernardo et al, 2010;Nakamura and Sadoshima, 2018;Oldfield et al, 2019). For example, LVH induced by swimming exercise training is an adaption for a chronic increase in hemodynamic overload (Xiao et al, 2014;Bernardo et al, 2018), whereas myocardial infarction induced pathological LVH is associated with increased fibrosis, lowered aerobic capacity, and maladaptive remodeling (McMullen and Izumo, 2006;Dorn, 2007;Schiattarella and Hill, 2015). The physiological LVH exerts cardioprotection in patients with cardiovascular diseases.…”

Lipidomic Profiles of the Heart and Circulation in Response to Exercise versus Cardiac Pathology: A Resource of Potential Biomarkers and Drug Targets

“…However, hypertrophy in response to a disease stimulus (e.g., hypertension) typi-cally progresses to heart failure and is associated with increased mortality in humans. In contrast, exercise-induced hypertrophy is reversible and has been linked with protection against cardiovascular disease (Bernardo et al, 2018a;Tham et al, 2015). There has been substantial interest in understanding the mechanisms that underpin the differences between exercise-induced physiological hypertrophy and disease-induced pathological hypertrophy, as this may lead to the identification of new therapeutic targets.…”

“…Numerous studies have described distinct functional, structural, and metabolic differences in settings of pathological and physiological hypertrophy (Bernardo et al, 2010). The distinct regulation of biochemical signaling pathways, mRNAs, microRNAs, and proteins have all been implicated in contributing to the distinct phenotypes (Bernardo et al, 2018a;Tham et al, 2015). A mechanism largely unexplored is the regulation of lipids.…”

Altered expression levels of autophagy-associated proteins during exercise preconditioning indicate the involvement of autophagy in cardioprotection against exercise-induced myocardial injury

“…Strategies that encourage endogenous cardiac adaptations have increasingly been used as non-pharmacological therapies to mitigate the risks of cardiovascular events. One example, known as cardiac preconditioning, involves vigorous exercise prior to ischemic events to prevent lethal myocardial injury [1][2][3][4]. Exercise preconditioning (EP), which consists of both short-term and long-term repeated intermittent exercise, can reduce myocardial injury caused by exhaustive, continuous highintensity exercise [1].…”