Exercise evokes profound changes in endocrine activity and whole body metabolism. The raised energetic demands require tissue-specific molecular exchanges to take place. Exercise-induced secretory factors or ‘exerkines’ are a mechanism of tissue cross-talk of growing popularity in research. This growth has seen them linked to an abundance of health benefits.
Physical activity is beneficial to the individual. This has been universally accepted for, give or take, a couple of thousand years. However, there is considerable mechanistic complexity underlying this most basic of statements. In particular, the high bar for understanding mechanisms of tissue-specific response to exercise has recently been further elevated. The identification of exercise-mediated release of secretory factors has been documented in most endocrine responsive tissues, including liver, muscle, adipose (brown and white), brain and bone. However, the functional roles of exerkines, their physiological impact and, in some cases, their very existence remain deeply contentious.
CELL–CELL ACTIONS
'When understanding biological impact versus incidental observation, causal links for exerkines remain limited.'
Recent studies have examined exerkines originating from a variety of skeletal muscle and adipose depots. Importantly, work in these tissues has identified white adipose changes in secretory profile in ageing humans. Though not in response to exercise, many of the prototypical secretory factors described as exercise-responsive were measured.1 Not all showed significant changes during ageing, but profiles from serum showed a modest number of significant events (including a reduction in insulin). These data suggest that tissue-specific secretions (at least in the context of human ageing) may serve to direct local cell–cell actions as opposed to wider systemic roles. This does raise questions about the numerous physiological roles ascribed to exerkines from murine-focused studies.
Experimental work correlating adipokines released with diseased status are common. However, the array of adipose depots available for analysis makes conclusions difficult to reconcile. Extrapolation of these findings to physiological importance represents a considerable challenge. Nevertheless, recent work has made some progress. For example, the adipokine CTRP9 increases in children experiencing type 1 diabetes, and FGF21 increases in those living with type 2 diabetes. This implies that these adipokines may be relevant to disease status.2 Moreover, the secretory factor resistin is hormonally regulated by vitamin D,3 and has been shown to have a causal relationship with atrial fibrillation.4 Again, these are not exercise-mediated actions, but hint at potential endocrine importance and indicate underpinning mechanisms.
EXERCISE-DEPENDENT METABOLITES
'Does the type of exercise influence the secretory factors produced by any given tissue? Perhaps, but no one knows, and there is substantial room for new studies to generate new knowledge.'
A recent, comprehensive study catalogued tissue-specific secretions over time. This revealed the acute sensitivity of organ responsiveness to exercise as well as its time-based nature.5 It provided considerable insight into the complexities at play, identifying 600–900 exercise-dependent metabolites, dependent upon the tissue. Of note is the identification of 2-hydroxybutyrate as a time-dependent exerkine, given that it is already known as a marker of insulin resistance.6
When understanding biological impact versus incidental observation, causal links for exerkines remain limited. Resolution of temporal studies can be problematic, limited by the sample collection times and intervals between them. However, together with the increased understanding of extracellular vesicles, a concept arises for such modulators of organ–organ cross-talk to be exploited for therapeutic use. But, to achieve this, it still needs to be proved beyond doubt that extracellular vesicles serve a particular function, as reviewed by Darragh et al.7
In addition, does the type of exercise influence the secretory factors produced by any given tissue? Perhaps, but no one knows, and there is substantial room for new studies to generate new knowledge. A similar situation applies regarding the subject of cell heterogeneity. The technology to answer these questions is now more accessible. Methodology for sampling secreted factors is a crucial point, often overlooked. Consistency and accurate reporting of protocols for the measurement of secretory factors require greater standardisation.
FUTURE CHALLENGES
Many years after initial detection, we still are yet to understand how exercise-induced secretory factors interact with endocrine function and impact whole-body physiology (if at all). As awareness increases and technological barriers decrease, there is a growing need to catalogue and validate emergent secretory factors (including cardiokines, osteokines and hepatokines).
All in all, we do understand that organs exhibit an element of cross-talk in response to physical exertion. The secreted elements termed exerkines may contribute to the beneficial impacts of exercise, though this remains to be demonstrated in humans. Moreover, emerging studies show the range of secretory factors released in response to exercise are probably tissue-specific and certainly circadian-influenced. Deconvoluting such responses represents a considerable scientific challenge.
Craig L Doig
Senior Lecturer in Metabolic Health, Department of Biosciences, Nottingham Trent University
REFERENCES
1. Trim WV et al. 2022 Journal of Physiology 600 921–947.
2. Arking A et al. 2022 Hormone Research in Paediatrics doi: 10.1159/000522665.
3. Šebunova N et al. 2022 BMC Endocrine Disorders 22 33.
4. Chen D et al. 2022 Journal of Clinical Endocrinology & Metabolism doi: 10.1210/clinem/dgac048.
5. Sato S et al. 2022 Cell Metabolism 34 329–345.
6. Gall WE et al. 2010 PLoS One 5 e10883.
7. Darragh IAJ et al. 2021 Frontiers in Physiology 12 738333.
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