The biochemical and metabolic adaptations underpinning the health benefits of exercise

1. Introduction

The field of exercise science is experiencing a renaissance, with recent research illuminating the molecular, cellular, and systemic effects of physical activity. This is largely due to the now unequivocal evidence that a lack of physical activity, not only has direct effects on the prevalence of non-contagious diseases (NCDs) but has profound additive effects of other risk factors for NCD such as obesity and hypertension.¹ The articles in this special topic of Journal of Sport and Health Science (JSHS) are dedicated to research on Exercise biochemistry & metabolism. Each article contributes unique perspectives on how exercise influences muscle adaptation, metabolic health, inter-organ communication, and metabolic disease risk. Collectively, these studies advance our understanding of the biochemical and molecular mechanisms underpinning exercise benefits and highlight promising avenues for future research and intervention. The impetus for such a special topic was inspired by a round table conversation by key leaders in the field held at the 2024 International Biochemistry of Exercise Conference (IBEC2024) held in Limerick, Ireland.

2. Molecular adaptations and skeletal muscle biochemistry and metabolism

A recurring theme is the profound impact of exercise on skeletal muscle at the molecular level. Frankenberg et al.² investigated heat shock proteins (HSPs) in young and older adults, revealing that aging is associated with higher phosphorylation of small HSPs—markers of cellular stress. Importantly, a 12-week high-intensity training (HIT) programme in older adults reduced these phosphorylation levels to those seen in younger individuals. Critically, this study suggests that targeted exercise can mitigate age-related cellular stress and potentially delay muscle decline, offering a practical intervention for healthy ageing. In keeping with the muscle biochemistry theme, Murach and Bagley³ provide a comprehensive review of “omics” approaches in skeletal muscle research. They detail how exercise alters the epigenome, transcriptome, and proteome, and discuss the promise of single-cell and spatial sequencing technologies. This is a timely and important overview because the field is starting to appreciate the power of multi- vs. single-omics platforms to enable a more nuanced understanding of exercise-induced adaptations in skeletal muscle and response heterogeneity, paving the way for personalized strategies to optimize muscle health and performance, particular in drug treatment and disease settings where sarcopenia, defined as age-related loss of skeletal muscle mass, strength, and function, is becoming increasingly problematic

3. Mitochondrial quality control and immune signaling

Khemraj et al.⁴ focus on mitochondrial quality control within skeletal muscle, emphasizing the link between muscle activity, mitochondrial health, and innate immune signaling. Chronic disuse leads to fragmented, dysfunctional mitochondria and heightened inflammation, while exercise promotes mitochondrial biogenesis and networking. The authors highlight the role of mitochondrial damage-associated molecular patterns (DAMPs) in activating the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, a protein complex that is a key component of the innate immune system, responsible for activating the inflammatory response. Importantly, this paper suggests that modulating muscle activity could be a therapeutic strategy for managing excessive inflammation and maintaining muscle function.

4. Inter-organ communication and metabolic adaptation

The systemic effects of exercise are further explored by Katayama et al.,⁵ who demonstrate that endurance training increases the microRNA (miR) miR-136-3p in exosome-enriched extracellular vesicles (EVs). EVs have emerged as a key mechanism by which organs share molecular cargo during exercise.⁶ The authors of the current study discuss how EVs facilitate communication between pancreatic islets and skeletal muscle, enhancing glucose uptake and myogenesis independently of insulin signaling. The identification of Nardilysin convertase (NRDC) as a direct target of miR-136-3p underscores the complexity of exercise-induced metabolic adaptation and highlights novel pathways for improving glucose regulation.

5. Cardiac health and obesity

Perera et al.⁷ examine the interplay between diet-induced obesity, voluntary exercise, and cardiac mitochondrial function in mice. The authors demonstrated that administering mice a high-fat diet impaired cardiac mitochondrial activity and reduced a particular and important lipid species, namely cardiolipins. This was an important observation because cardiolipins are essential for mitochondrial respiration. Moreover, voluntary exercise training reversed these effects, inducing physiological cardiac hypertrophy and enhancing mitochondrial function. These findings reinforce the cardioprotective role of exercise in obesity and suggest that targeting mitochondrial health may be key to preventing obesity-related cardiovascular disease.

6. Intergenerational benefits of exercise

Exercise training has significant intergenerational impacts, with parental activity directly benefiting offspring’s brain health, cognition, biochemical and metabolic profile, often through epigenetic changes affecting gene expression in the offspring. The intergenerational impact of physical activity is elegantly demonstrated by Alves-Wagner et al.⁸ Their study shows that grandmaternal exercise improves glucose metabolism and insulin sensitivity in second-generation offspring, with more pronounced effects in males. These benefits occur despite no changes in body weight or composition, indicating that exercise during pregnancy can confer metabolic advantages across generations via epigenetic and tissue-specific mechanisms.

7. Comparing exercise modalities in obesity and diabetes

Shute et al.⁹ provide a direct comparison of endurance and resistance exercise in the context of obesity and diabetes. Both modalities limit fat mass gain, but resistance training (weightlifting) offers superior improvements in insulin sensitivity. Endurance training enhances exercise capacity and muscle weight, while resistance training more effectively reduces visceral and subcutaneous fat. These results suggest that resistance exercise may be particularly beneficial for improving glycemic control in obesity.

8. Synthesis and future directions

Taken together, these 7 papers offer a panoramic view of exercise biochemistry and metabolism, from molecular mechanisms to systemic and intergenerational effects. The research underscores the transformative potential of physical activity for muscle health, metabolic regulation, immune function, and disease prevention. Key themes include:

• •The capacity of exercise to reverse age-related cellular stress and modulate molecular pathways in muscle.
• •The importance of mitochondrial quality control and immune signaling in muscle adaptation.
• •The role of EVs and miRs in inter-organ communication and metabolic health.
• •The cardioprotective effects of exercise in obesity, mediated by improvements in mitochondrial function.
• •The remarkable intergenerational benefits of maternal physical activity.
• •The differential impacts of endurance and resistance exercise on adiposity and insulin sensitivity.

As the field advances, integrating multi-omics technologies, refining exercise modalities, and exploring intergenerational and systemic effects will be crucial. These studies collectively highlight the need for continued innovation and collaboration to translate mechanistic insights into effective interventions for health and disease across the lifespan.

Declaration of competing interest

Both authors declare that they have no competing interests. Given their both roles as board members, RMM and MAF had no involvement in the peer review of this article and had no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to another journal editor.