CrossTalk proposal: Exercise training intensity is more important than volume to promote increases in human skeletal muscle mitochondrial content

Abstract

Mitochondria are vital organelles for health and performance that display remarkable plasticity, particularly in response to changes in contractile stimuli (Hood et al. 2019). Exercise training increases the abundance of skeletal muscle mitochondria (Holloszy, 1967; Morgan, 1971), as assessed by mitochondrial fractional area, respiration, enzyme activity and protein content, among other measures (Larsen et al. 2012). Given the associations between skeletal muscle mitochondrial content, exercise capacity and health (Holloszy, 1967; Hood et al. 2019), examining the responsiveness of mitochondria to various exercise stimuli is critical for understanding physiological regulation and providing evidence-based exercise prescription in athletic and clinical settings. While the responsiveness of skeletal muscle mitochondria to different exercise stimuli has been addressed in several systematic rodent studies (e.g. Fitts et al. 1975; Hickson, 1981; Dudley et al. 1982), the focus of this exchange is humans, as rodent data do not necessarily translate to humans and cannot directly inform exercise prescription. Exercise-induced increases in mitochondrial content are influenced by a number of training variables, such as the duration, frequency and volume of exercise (MacInnis & Gibala, 2017); however, we contend that intensity is the most important variable mediating exercise-induced increases in mitochondrial content in human skeletal muscle within a fixed period of time (e.g. several weeks or months). This view is primarily supported by acute investigations of exercise-induced changes in intracellular signalling pathways that promote mitochondrial biogenesis and studies comparing changes in mitochondrial content after different training interventions. The latter point is particularly informed by work-matched comparisons of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), as well as comparisons of low-volume sprint interval training (SIT) and higher volume MICT protocols (MacInnis & Gibala, 2017). Secondary to our view that the available biological evidence supports our argument, we contend that exercise intensity is more important than training volume for pragmatic reasons such as efficiency. Mitochondrial biogenesis is largely regulated by changes in metabolite concentrations and biochemical processes that feed into molecular pathways that increase the expression of relevant genes and subsequently the synthesis of mitochondrial proteins (Egan & Zierath, 2013; MacInnis & Gibala, 2017; Hood et al. 2019). Higher intensity exercise elicits larger increases in metabolites such as H+, ADP, AMP, Pi, creatine and lactate, owing to greater rates of ATP hydrolysis and substrate-level phosphorylation (Sahlin et al. 1987, 1989; Howlett et al. 1998). Downstream kinases related to mitochondrial biogenesis, including AMP-activated protein kinase (AMPK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII), are also activated (phosphorylated) to a greater extent following higher intensity exercise (Wojtaszewski et al. 2000; Egan et al. 2010). The mRNA expression of peroxisome proliferator activated receptor γ coactivator 1⍺ (PGC1⍺) in particular is increased more after high-intensity exercise compared to work-matched low-intensity exercise, owing in part to the greater activation of activating transcription factor-2 (ATF-2) and histone deacetylase 4 (HDAC4) (Egan et al. 2010) and reduced methylation in the promoter regions of PGC1⍺ and related genes (Barres et al. 2012). A single session of low-volume, sprint-type exercise also activates AMPK, CaMKII and p38 mitogen activated protein kinase (MAPK), among other signalling molecules, and robustly increases the expression of PGC1⍺ despite the low volume of exercise (Gibala et al. 2009; Metcalfe et al. 2015; Skelly et al. 2017; Fiorenza et al. 2018). Further, Fiorenza et al. (2018) reported that a low-volume sprint protocol (6 × 20 s ‘all-out’) elicited increases in gene expression and intracellular signalling that were similar or greater than those elicited by a 50 min bout of moderate-intensity continuous cycling involving 8 times more work. Other putative signalling events seem to occur above an intensity threshold, such as the fragmentation of the ryanodine receptor 1 protein (RYR1), which was elicited by supramaximal exercise but not lower intensity exercise (Place et al. 2015). Finally, the exercise-induced increase in mitochondrial protein fractional synthesis rate was greater after higher- compared to lower-intensity exercise when total work was matched (Di Donato et al. 2014). Overall, various levels of the mitochondrial biogenesis pathway are sensitive to exercise intensity. Short-term, single-leg HIIT elicited greater increases in citrate synthase (CS) maximal activity and mitochondrial respiration as compared to work-matched MICT performed with the other leg (MacInnis et al. 2017). Daussin et al. (2008) also reported greater mitochondrial respiration in response to HIIT as compared to MICT based on a crossover design. The results of these studies are particularly instructive, since training responses were compared within the same individual, reducing the influence of confounding factors. Some studies comparing work-matched HIIT and MICT in different groups of individuals have reported similar increases in succinate dehydrogenase (SDH) maximal activity (Henriksson & Reitman, 1976) and CS maximal activity (Baekkerud et al. 2016) or no change in CS maximal activity (Granata et al. 2016), whereas another study demonstrated a larger increase in PGC1⍺ protein content after work-matched HIIT compared to MICT (Tjonna et al. 2008). Some of the strongest evidence in favour of exercise intensity comes from studies in which SIT increased mitochondrial content to a similar extent as MICT despite a lower total exercise volume (Burgomaster et al. 2008; Scribbans et al. 2014; Gillen et al. 2016). For example, Gillen et al. (2016) reported similar increases in CS maximal activity after 12 weeks of SIT or MICT, despite a fivefold difference in volume: the former training protocol involved 3 × 20 s of ‘all-out’ cycling over 10 min, whereas the latter protocol involved 50 min of continuous moderate-intensity cycling per session (Gillen et al. 2016). Finally, the relationship between exercise intensity and training volume is not necessarily reciprocal: whereas a high exercise intensity can ‘compensate’ for a low training volume and increase mitochondrial content robustly, a high volume of exercise does not necessarily increase mitochondrial content without sufficient intensity (Helge et al. 2008). In addition to the preceding arguments, exercise intensity is more important from a pragmatic perspective. Higher-intensity exercise increases mitochondrial content quickly (Gibala et al. 2006; MacInnis et al. 2017) and often with a smaller time commitment than lower-intensity exercise (Burgomaster et al. 2008; Gillen et al. 2016). Furthermore, without increasing the time commitment, exercise intensity can be increased to provide a progressive training stimulus, which may be necessary to continually augment mitochondrial content (Egan et al. 2013); however, achieving a greater training load by increasing the duration or frequency of exercise implies a greater time commitment, which may be impractical, especially for those mainly seeking to enhance health (Gillen & Gibala, 2014). We are not arguing that lower intensities of exercise are ineffective: prolonged exercise at lower intensities activates mitochondrial biogenesis, albeit perhaps in response to different intracellular signals (Fiorenza et al. 2018), and increases mitochondrial content (Burgomaster et al. 2008; Gillen et al. 2016). Yet, per unit time, higher intensity exercise is generally more effective for increasing mitochondrial content, making it more time efficient. Finally, the term ‘high-intensity’ is relative, not absolute, meaning high-intensity exercise can be individualized to suit various populations (Tjonna et al. 2008). The biochemical processes promoting mitochondrial biogenesis are mediated by exercise intensity, and higher intensities of exercise generally elicit greater increases in mitochondrial content than lower intensities per unit of time or work. Given the available biological evidence and practical considerations, we contend that exercise intensity is the most important variable with respect to increasing skeletal muscle mitochondria content in humans. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘LastWord’. Please email your comment, including a title and a declaration of interest, to [e-mail]. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. The authors are interested in understanding the mechanisms regulating human physiological responses to acute and chronic exercise and the factors mediating these responses, such as nutrition, sex and the environment. Martin MacInnis is an Assistant Professor in the Faculty of Kinesiology at the University of Calgary, where he is investigating integrative physiological responses to exercise and hypoxia in humans. Lauren Skelly is currently completing her PhD at McMaster University, where she is exploring skeletal muscle adaptations in response to endurance and interval exercise training. Martin Gibala is Professor and Chair of the Department of Kinesiology at McMaster University. He studies the regulation of skeletal muscle metabolism, including the impact of exercise and nutrition on human health and performance. Martin MacInnis (postdoctoral fellowship) and Lauren Skelly (PhD) trained under the supervision of Martin Gibala. 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 authors declare that they have no competing interests. M.J.M., L.E.S. and M.J.G. contributed equally to the writing and critical revision of this manuscript. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The research programmes of M.J.M. (ID: RGPIN-2018-0 6424) and M.J.G. (ID: RGPIN-2015-0 4632) are funded through Discovery Grants from the Natural Sciences and Engineering Research Council of Canada (NSERC). L.E.S. is funded by an NSERC Vanier Canada Graduate Scholarship.