Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?

Abstract

Impaired exercise capacity is the key symptom of heart failure (HF) and is associated with reduced quality of life and higher mortality rates. Unfortunately, current therapies, although generally lifesaving, have only small or marginal effects on exercise capacity. Specific strategies to alleviate exercise intolerance may improve quality of life, while possibly improving prognosis as well. There is overwhelming evidence that physical exercise improves performance in cardiac and skeletal muscles in health and disease. Unravelling the mechanistic underpinnings of exercise-induced improvements in muscle function could provide targets that will allow us to boost exercise performance in HF. With the current review we discuss: (i) recently discovered signalling pathways that govern physiological muscle growth as well as mitochondrial quality control mechanisms that underlie metabolic adaptations to exercise; (ii) the mechanistic underpinnings of exercise intolerance in HF and the benefits of exercise in HF patients on molecular, functional and prognostic levels; and (iii) potential molecular therapeutics to improve exercise performance in HF. We propose that novel molecular therapies to boost adaptive muscle growth and mitochondrial quality control in HF should always be combined with some form of exercise training.

Keywords: Cardiac and skeletal muscle; Exercise intolerance; Exercise training; Heart failure; Mitochondrial adaptation; Physiological muscle hypertrophy.

Figure 1

Physiological adaptation in cardiac and skeletal muscle. (A) The adaptive effects of endurance exercise on cardiac muscle are governed by special signal transduction pathways and mitochondrial quality control. Upper panel: exercise stimulates binding of insulin‐like growth factor 1 (IGF1) to a specific transmembrane tyrosine kinase membrane receptor (IGF1R), causing a conformational change that recruits and phosphorylates insulin receptor substrates 1 and 2 (IRS1/2). In turn, the activation of IRS1/2 phosphorylates phosphoinositide 3 kinase (PI3K) and further downstream activation of protein kinase B (Akt). The diverse effects of Akt activation include for example activation of endothelial nitric oxide synthase (eNOS), activation and/or inhibition of sirtuins, inhibition of glycogen synthase kinase 3β as well as inhibition of forkhead box protein O3 (FOXO3). Most importantly, however, activation of Akt subsequently (i) promotes protein synthesis through activation of mammalian target of rapamycin complex 1 (mTORC1), its downstream activation of ribosomal protein S6 kinase 1 (S6K1) and inhibition of eIF4E‐binding protein 1 (4EBP1) and (ii) by inhibiting the transcriptional repressor CCAAT/enhancer binding protein‐β (C/EBPβ) to activate a specific physiological growth programme downstream of the transcription factor CBP/p300‐interacting trans activator 4 (CITED4). Lower panel: exercise also enhances mitochondrial performance through enhanced mitochondrial biogenesis, and potentially also through increased mitochondrial clearance (mitophagy) and mitochondrial morphological changes (mitochondrial dynamics). Exercise stimulates mitochondrial biogenesis through activation of AMP‐activated protein kinase (AMPK) and upregulation of sirtuin 1/3 (SIRT1/3) and eNOS. These factors in turn promote the activity of the transcription factor peroxisome‐proliferator‐activated‐receptor gamma coactivator 1‐alpha (PGC‐1α) and its downstream factors nuclear respiratory factor 2 (NRF2) and mitochondrial transcription factor A (tFAM). NRF2 and tFAM are both essential for the generation of new mitochondrial proteins. (B) Resistance exercise induces skeletal muscle hypertrophy mediated through Akt, which activates mTORC1 leading to the synthesis of new proteins and muscle growth. (C) In skeletal muscle, endurance exercise causes an increase in mitochondrial biogenesis, mitophagy and mitochondrial dynamics. Mitochondrial biogenesis is regulated by activation of AMPK, PGC‐1α and downstream NRF2 as well as tFAM. An additional effect of exercise in skeletal muscle fibres includes a shift toward a more oxidative composition through calcineurin (CnA) mediated activation of nuclear factor of activated T‐cells (NFAT) and Ca²⁺/calmodulin‐dependent protein kinase (CaMK), or through modulation of AMPK and PGC‐1α. Full lines indicate direct effects, dashed lines indicate indirect effects. AMP, adenine nucleotide monophosphate; ATP, adenine nucleotide triphosphate; C, cytoplasm; Ca²⁺, calcium; ER, endoplasmic reticulum; M, mitochondria; miR‐222, microRNA; N, nucleus.

Figure 2

Mechanistic underpinnings of exercise intolerance in heart failure (HF) and the adaptive effects of exercise. Exercise intolerance can develop due to central and/or peripheral factors, which often include pathological cardiac remodelling and mitochondrial dysfunction. These processes can be attenuated by performing exercise, which causes adaptive effects in a disease setting in both cardiac and skeletal muscle. The mechanisms involved include growth signalling as well as mitochondrial quality control. Colours have been used structurally: red indicates effects in HF, green indicates effects of exercise training. Full lines indicate direct effects, dashed lines indicate indirect effects. ATP, adenine nucleotide triphosphate; C, cytoplasm; DRP1, dynamin‐1‐like protein; Fis1, mitochondrial fission 1 protein; Mfn1‐2, mitofusin 1 and 2; N, nucleus; NRF1‐2, nuclear respiratory factors 1 and 2; OPA1, optical atrophy protein 1; PGC‐1α, peroxisome‐proliferator‐activated‐receptor gamma coactivator 1‐alpha; PINK1, PTEN‐induced kinase 1; ROS, reactive oxygen species; tFAM, mitochondrial transcription factor A.

Figure 3

Exercise as a molecular therapy for heart failure‐associated exercise intolerance. The adaptive effects of exercise in both health and disease may provide therapeutic targets to improve exercise intolerance in heart failure. The underlying mechanistic pathways involve stimulation of physiological cardiac growth, skeletal muscle hypertrophy and enhanced mitochondrial quality control. This is accompanied by inhibition of pathological cardiac growth, skeletal muscle atrophy and mitochondrial dysfunction. These exercise‐induced effects can be enhanced by targeting these pathways with pharmacological manipulation, diets/supplements and/or genetic targeting.