Insights into the influence of high‐intensity interval training on skeletal muscle clock gene expression in insulin‐resistant individuals

Skeletal muscle tissue plays a crucial role in movement, posture, thermogenesis and whole-body energy metabolism. For instance, skeletal muscle is a key insulin-sensitive metabolic tissue, accounting for up to 80% of postprandial glucose. Given its abundance and vital functions, it is not surprising that skeletal muscle plasticity is an important determinant of human health and disease. It is important to note that skeletal muscle is a heterogeneous tissue that exhibits a remarkable capacity to adapt to a wide range of physiological and pathological conditions, undergoing changes in size, fibre composition and metabolic properties. This adaptability is precisely what the term ‘skeletal muscle plasticity’ refers to; the muscle's ability to modify its structure and function in response to a variety of stimuli, such as changes in metabolic demand (activity vs. rest), nutritional state (fed vs. fasted) and environmental time cues (light vs. dark cycles). As such, healthy skeletal muscle can rapidly adapt to energy demands in response to various stimuli such as exercise training. While we have extensive knowledge regarding the structural and functional adaptability of healthy skeletal muscle, our understanding of plasticity in muscle affected by disease remains limited. All organisms possess a circadian clock to facilitate physiological adaptation between day and night cycles. Peripheral tissues, like skeletal muscle, have their own self-regulating molecular clock, governed by transcription and translation feedback loops. This molecular clock regulates many genes that play a critical role in maintaining both muscle and overall systemic health. Among these genes, Bmal1 and Clock play a significant role, orchestrating the regulation of thousands of target genes, including their repressors, such as ‘period’ genes (Per1, Per2 and Per3) and cryptochrome genes (Cry1 and Cry2). Any disruption of those genes can have adverse effects on skeletal muscle plasticity. Consistent with this, Dr Stefano Schiaffino's lab showed that muscle-specific inactivation of Bmal1 in mice triggered muscle insulin resistance and impaired glucose metabolism (Dyar et al., 2014). Additionally, in humans, skeletal muscle Bmal1 expression significantly increases after a 12-week aerobic exercise training programme in elderly individuals with obesity and prediabetes (Erickson et al., 2020). This leads to the intriguing question: how are changes in the skeletal muscle clock machinery connected to metabolic improvements induced by exercise? There is a growing body of evidence supporting the notion that aerobic training, particularly high-intensity interval training (HIIT), offers numerous health benefits in both healthy individuals and those with chronic illnesses (Atakan et al., 2021). These health benefits encompass improvements in aerobic capacity, skeletal muscle function, mitochondrial health and insulin sensitivity. However, exactly how HIIT influences the circadian rhythm is poorly understood, especially in overweight/obese individuals dealing with metabolic disorders. In a recent study published in the Journal of Physiology, Harmsen and colleagues investigated whether 12 weeks of HIIT could influence the expression of clock genes and improve skeletal muscle mitochondrial respiration as well as whole-body glucose metabolism in obese and insulin-resistant men (Harmsen et al., 2023). As expected, the authors report data showing that participants improved their overall health, as indicated by improvement in aerobic fitness (e.g. VO2 max). Moreover, the authors observed that three sessions of HIIT per week over a 12-week period have a positive effect on body composition, including a reduction of fat mass percentage and an increase in the fat-free mass percentage. These findings highlight the potential benefits of HIIT not only for aerobic fitness but also for body composition in obese/insulin-resistant men. Using whole-room indirect calorimetry during sleep periods and ventilated hood measurements every 5 h, Harmsen and colleagues also reported data on sleeping metabolic rate, respiratory exchange ratio and 24 h substrate metabolism. The authors observed that HIIT did not have a significant impact on whole-body substrate oxidation and energy expenditure. In turn, these experimental data confirmed defects in fuel switching (e.g. inability to switch to fat oxidation) during the night in obese/insulin-resistant men when compared with healthy young men from another study (Wefers et al., 2020). Taken together, the findings collected by Harmsen and colleagues provide evidence that 12 weeks of HIIT does not improve metabolic flexibility in a population of obese and insulin-resistant men. Metabolic flexibility refers to the ability of an organism, an organ or an individual cell to adjust its fuel oxidation in response to variations in metabolic or energy demands. The underlying mechanisms that regulate metabolic flexibility are still not completely understood, and it is likely that proper mitochondrial function has a key role to play in the regulation of metabolic flexibility. Given that metabolic flexibility can be influenced by several factors, it would be interesting in future research to examine other populations with differences in age, sex, ethnicity and the presence or absence of pre-existing metabolic diseases. Furthermore, it may be of interest to determine a longer time course (e.g. 48 h) of whole-body substrate oxidation and energy expenditure to further understand the functional importance of circadian rhythms in regulating metabolic processes. One of the notable strengths of the Harmsen et al. study is the diverse range of approaches used to investigate metabolic adaptations and skeletal muscle circadian function in response to HIIT. For instance, pre-and post-training serial skeletal muscle biopsies from the vastus lateralis were performed to assess the impact of clock gene expression and mitochondrial respiration in permeabilized muscle fibres. To examine the impact of HIIT on skeletal muscle clock gene expression, the authors measured mRNA expression of various clock genes, including Bmal1, Clock, Reverbα, Rorα, Per1, Per2, Per3 and Cry1. As expected, most of those genes displayed marked day–night differences. In response to HIIT exercise training, the authors observed that only Clock and Rorα mRNA expression was downregulated as compared with baseline. It is worth mentioning that the authors report a significant interaction (time × exercise) of Per1 and Per3 genes. Taken together, these results indicate that HIIT has a modest impact on clock genes. However, this does not necessarily imply that there are no differences at the protein level. Therefore, future research should aim to investigate the relationship between mRNA and protein expression over time, particularly in response to HIIT. Another important finding of the study is the marked improvement in mitochondrial oxidative capacity in skeletal muscle in response to HIIT at two time-points (13h30, 23h30). It is interesting to note that there is no difference in mitochondrial respiration rate over the time of the day (8h30, 13h30, 23h30). While the authors observed that exercise training significantly increased all mitochondrial respiration states, they did not assess any marker of mitochondrial content. As such, it is still unclear whether HIIT improved qualitative adaptations of mitochondrial function in skeletal muscle from obese and insulin-resistant men. Therefore, future studies may also consider assessing mitochondrial quality (mitochondrial function/content). Additionally, it is important to question whether the findings reported by Harmsen and colleagues are linked to changes in muscle fibre typology. Since different muscle fibre types exhibit distinct metabolic characteristics, changes in fibre typology could potentially influence mitochondrial function. Currently, the interplay between fibre typology, clock gene expression and mitochondrial function remains unclear. Finally, it would be interesting to also investigate the impact of other exercise modalities on whole-body metabolism, skeletal muscle molecular clock, mitochondrial function, myofibre typology in both men and women from different age groups and stages of metabolic diseases. These future investigations would enhance our understanding of the skeletal muscle molecular clock and how sex, age and metabolic health status (e.g. prediabetes vs. diabetes) influences the metabolic adaptations following different exercise modalities. 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. None declared. K.D.: 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 and agreement to be accountable for all aspects of the work. S.T.: 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 and agreement to be accountable for all aspects of the work. L.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 and agreement to be accountable for all aspects of the work. V.C.: 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 and agreement to be accountable for all aspects of the work. J.-P. L.-G.: 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 and agreement to be accountable for all aspects of the work. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. The authors apologise for not citing all relevant articles due to reference limitations of the Journal Club format.