What's so special about the physiology of exercise? This Special Issue!

Why do papers dealing with exercise feature so prominently in The Journal of Physiology? Perhaps it is simply because exercise requires so many changes to physiology, that it serves, in its various forms – strong, weak, intermittent, continuous, isometric, isotonic or even imaginary – as a means of interrogating how diverse physiological systems operate, both in isolation and together. Indeed, how the cardiovascular system is engaged during exercise, and how it interacts with control of the working muscles, is an important area of research, covering as it does molecular, cellular, systems and integrative physiology. This Special Issue covers many of these aspects, and builds on a symposium organised by Yoshihiro Kubo – Regulation of cardiovascular and skeletal muscle function during exercise – at the Federation of Oceanic and Asian Physiological Societies (FAOPS) congress in Deagu, South Korea, on 1–4 November 2023, and a symposium – Neural control & autonomic regulation during exercise: recent innovations – organised by Satoshi Koba and Marc Kaufman at The International Society for Autonomic Neuroscience (ISAN) meeting held in Birmingham, UK, on 24–27 July 2024. I am very grateful to Yoshihiro and Marc for serving as Reviewing Editors for this Special Issue, with the open call for manuscripts leading to several being submitted de novo. This is an important feature of our special issues: in addition to invited submissions we open it up to the community to truly reflect the 'state-of-the-art' of work in the field. Importantly, the rigour with which Yoshihiro and Marc handled manuscripts meant that only the best made it to publication. So, here you have it: 21 papers published online over the last year and earlier this year now available in one handy volume for your reading pleasure. Starting at the molecular level, Takeuchi and Matsuoka (2024) consider how exercise affects the energetics of individual muscle cells in the heart, and the role of mitochondria in calcium release from the sarcoplasmic reticulum. The authors developed a model of the human ventricular myocyte, building in all the features of the known energy-dependent processes involved in excitation–contraction, and investigated how mitochondria located in close proximity to the sarcoplasmic reticulum, facilitate these processes during exercise, particularly via mitochondrial Ca2+ uniport activity–RyR. Still in the heart, Phadke et al. (2024) consider the implications of exercise on the heart in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), in whom atrial arrhythmias also have a high prevalence. Variations in a gene expressed in the desmosomes of the heart, plakophilin-2 (PKP2), feature prominently in this disease, so, using a PKP2 knock-out mouse model, the authors show that despite there being no changes in intracellular Ca2+ dynamics or action potential morphology, atrial cardiomyocytes in the knock-out mice showed enhanced sarcomere shortening and impaired sarcomere relaxation, exacerbated by the selective β adrenoreceptor agonist isoproterenol. The authors suggest that this may contribute to exercise-induced atrial fibrillation in patients with PKP2-related ARVC. Moving onto integrative studies in experimental animals, this issue contains several papers that investigate how the cardiovascular and skeletomotor systems interact during exercise. By examining the brain, Narai et al. (2024) show that orexin-containing neurones in the hypothalamus of the rat are activated during voluntary exercise (wheel-running) and go on to show using optogenetic techniques that light-induced activation of these neurones causes an increase in locomotion, heart rate (HR) and blood pressure (BP) in awake animals, together with an increase in sympathetic outflow recorded directly from renal nerves in anaesthetised animals. The authors thereby provide compelling evidence for an important role of the orexinergic system as a hub in sending the motor command system to other areas of the brain involved in the cardiovascular adjustments in exercise. In addition to central command, reflex inputs from the contracting muscles also play important roles in generating the increases in BP during exercise – the exercise pressor response (EPR). This is known to be augmented in patients with type 2 diabetes mellitus (T2DM), in which the actions of insulin are blunted. In a rat model of this disease, Estrada et al. (2024) show that insulin within the brain is reduced, but that injecting insulin directly into the vesicles of the brain reduced the increases in renal sympathetic nerve activity (RSNA) and BP induced by electrically evoked muscle contractions, essentially normalising the exercise pressor response. This strongly suggests that insulin within the brain contributes to cardiovascular control during exercise. Moreover, Huo et al. (2024) show that the exaggerated EPR to electrically evoked contractions in rats with T2DM is reduced by pharmacological blockade of the pro-inflammatory cytokine interleukin-1β (IL-1β), while activating the receptors augments the EPR. Given that circulating levels of IL-1β are higher in rats with T2DM, the authors suggest that inflammatory cytokines contribute importantly to the exaggerated BP responses to exercise in this disease. Ducrocq, Anselmi, Stella et al. (2024) and Ducrocq, Anselmi, Ruiz-Velasco & Kaufman (2024) utilise pharmacological tools to drill down into the underlying reflex components of the EPR, the metaboreflex and the mechanoreflex. In the first paper, the subject of a Perspectives article by Grotle and Stone (2024), the authors investigated the role of a specific TRP channel (TRPC6) – present on small-diameter myelinated (group III) muscle afferents – in the EPR, finding that the increase in RSNA and BP during electrically evoked contractions is reduced by blockade of TRPC6, while the increase in BP, but not RSNA, is augmented by increasing the activity of TRPC6. Interestingly, passive muscle stretch – known to increase RSNA and BP through the mechanoreflex – was also reduced by pharmacological blockade of the channel, but augmenting its activity increased both RSNA and BP. The authors conclude that TRPC6 channels play an important role in evoking the mechanical component of the EPR (Ducrocq, Anselmi, Stella et al., 2024). In their second paper (Ducrocq, Anselmi, Ruiz-Velasco & Kaufman, 2024) – the subject of a Perspectives article by Butenas (2024) – the team show, using a similar experimental protocol, that lactate and H+ accumulation increase RSNA and BP during electrically evoked contractions in which blood flow is occluded, but not during freely perfused contractions, and that this is abolished in rats in which the myophosphorylase gene (pygm) is knocked out. The authors argue that muscle acidosis contributes importantly to evoking the metaboreflex component of the EPR. Back to the mechanoreflex: Butenas et al. (2024) examined the role of thromboxane A2 and bradykinin B2 receptors located on the sensory endings of small-diameter muscle afferents on the mechanoreflex, known to be augmented in heart failure with reduced ejection fraction (HF-rEF). The authors showed that the increases in RSNA and BP produced by passive muscle stretch can be reduced by the PKCε translocation inhibitor PKCe141, while blockade of the IP3 receptor had no effect, suggesting that PKCε may play an important role in the exaggerated sympathetic response to exercise in HF-rEF. Clearly, much can be learnt from animal models, a fact highlighted in a comprehensive review by Kim et al. (2025). The authors discuss different approaches to studying aerobic exercise in mice, such as voluntary wheel running or forced treadmill running, and compare the metabolic profiles of aerobic and resistance training. They also consider the mechanisms underlying conversion of white fat to brown and – a particularly hot topic – the role of the gut microbiota in contributing to the beneficial metabolic effects of exercise. In addition to these detailed investigational studies in animal models, this Special Issue also features several excellent papers that have examined the cardiovascular adjustments during exercise in humans. First off is a study that examined the contribution of peripheral chemoreceptors to the control of blood flow to working muscle in people with hypertension. Using intravenous administration of low levels of dopamine to inhibit the peripheral chemoreceptors, as stimulated by breathing an hypoxic gas mixture, Sayegh et al. (2024) show that the peripheral chemoreceptors are tonically active at rest and limit the normal increases in blood flow to contracting muscle. In other words, in the absence of peripheral chemoreceptor input, blood flow increases to contracting muscle, suggesting that the compromised muscle blood flow responses in hypertension may in part be due to inputs from the peripheral chemoreceptors, as discussed further in a Perspectives article by D'Souza & Stickland (2024). A paper by Wan et al. (2024) goes further into the effects of hypoxia on exercise, showing a reduction in cerebral perfusion along with an increase in muscle sympathetic nerve activity (MSNA). Moreover, they see the opposite when exercising during hypercapnia: cerebral perfusion increases and MSNA is reduced. The authors suggest that these findings support a potential role of Cushing's mechanism, in which a low cerebral perfusion leads to an increase in MSNA and BP. How the cardiovascular and muscular systems interact in humans is explored in terms of network physiology by Garcia-Retortillo and Ch Ivanov (2024). The authors performed cross-correlation analysis between different spectral components of the EMG activity of leg and back muscles and the co-registered ECG, uncovering cardio-muscular network interactions that decline during fatigue. A Journal Club article by Langan (2025) on this paper points out that it makes sense for there to be a physiological link between muscle and cardiac activity, with high temporal coordination allowing efficient muscle activity. Of course, the brain is likely to be behind all of this, as explored by Bruce et al. (2025). These authors implemented virtual reality into their experimental design, showing that an increase in perceived effort during cycling exercise brings about appropriate cardiovascular responses to exercise; Bartman et al. (2025) elaborate on the elegant experimental design in a Perspectives article. And when it comes to muscle itself, Kaluhiokalani et al. (2024) show that a simple intervention – passive muscle heating – can increase muscle blood flow to a similar extent as seen during exercise, with endothelial nitric oxide synthase also increasing in both conditions. However, passive heat therapy did not improve muscle performance, no doubt because only exercise increases angiogenesis. Another paper considers the role of androgens in determining muscle mass, strength and performance following a 3 month period of resistance training in pre-menopausal females. By studying muscle biopsies, Alexander et al. (2024) show that the proportion of nuclear-localised androgen receptors, rather than resting levels of testosterone itself, largely account for the increases in muscle mass and strength following training in women. A Perspectives article by Hunter (2024) emphasises the roles of androgen receptors in the marked sex differences in human physical performance, and the changes that occur in males during puberty. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author has no competing interests. V.M.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. No funding was obtained.