Exercise Is Medicine…and the Dose Matters

Abstract

The cellular events underpinning exercise adaptation have long been studied since Holloszy's novel findings in rodents over 50 years ago (Holloszy, 1967). Contemporary advances in laboratory techniques have allowed researchers to further explore physiological adaptations to physical activity, and much attention has been given to elucidating the distinct biochemical responses to exercise of varying intensities. More specifically, comparison of high intensity interval training (HIIT) or sprint interval training (SIT), to moderate intensity continuous training (MICT) has been an area of great interest among exercise physiologists. Spearheading these investigations, Burgomaster and colleagues provided evidence for robust and comparable metabolic adaptations when 6-weeks of low-volume SIT was pitted against conventional MICT, despite markedly reduced total training volume in the SIT group (66% less time, 90% less energy expenditure) (Burgomaster et al., 2008). Follow-up studies supporting these findings have provided continued enthusiasm for HIIT/SIT as a time-efficient strategy to improve cardiometabolic health (Gillen and Gibala, 2014; Gillen et al., 2016; Wolfe et al., 2020). HIIT has since become one of the most popular fitness trends as reported by the American College of Sports Medicine (ACSM) (#5 in 2021 survey) (Thompson, 2021). While we acknowledge these findings and are advocates for HIIT, we feel as though it is also important to appreciate the discrepant nature of HIIT and MICT, which may foster unique physiological adaptations with relevant health implications. Few, if any of these adaptations are mutually exclusive, but their magnitude may vary in a manner that should be considered to when determining exercise prescription. Cardiorespiratory fitness (i.e., VO₂max) is an independent predictor of cardiovascular and all-cause mortality (Myers et al., 2002) and sets the upper limit for aerobic metabolism (Joyner, 1991; Joyner and Coyle, 2008), justifying its use as an endpoint for studies comparing HIIT vs. MICT. By in large, most (Burgomaster et al., 2008), but not all (Gillen et al., 2016; Gerosa-Neto et al., 2019), studies show greater improvements in VO₂max with HIIT vs. MICT (Milanović et al., 2015) (Helgerud et al., 2007). For example, in an 8-week training study Helgerud and colleagues observed significantly greater improvements in VO₂max (~4-5ml/kg/min), cardiac output (~3L/min), and stroke volume (~15ml/beat) with HIIT [~95% max heart rate (MHR)] vs. MICT (70% MHR) (Helgerud et al., 2007). Similar findings were seen in obese men and women where the 4 × 4-min group had greater VO₂max gains (10%) compared to 10 × 1-min (3.3%) or 45-min of MICT (3.1%) (Bækkerud et al., 2016), but differs from the results of Morales-Palomo using equivalent exercise dosages in those with metabolic syndrome (MetS), where all groups improved equally (~12%) (Morales-Palomo et al., 2019). However, given the documented role of central factors in limiting maximal oxygen consumption (Saltin, 1985), it seems reasonable that efforts limited by VO₂max would preferentially promote central cardiovascular adaptations. An important consideration is the potential for diminishing returns (Tjønna et al., 2013) and cardiac complications (O'keefe et al., 2012) with excess volumes of high intensity endurance training. In untrained but otherwise healthy subjects, Tjonna and colleagues demonstrated that a single 4-min high intensity treadmill bout 3x/week elicited equivalent improvement in VO₂max (~10%) as the same workload repeated four times per session (Tjønna et al., 2013). Further, it should be noted that extreme high intensity training volumes undertaken in a small subset of endurance athletes may be deleterious to heart health (O'keefe et al., 2012). Nonetheless, the inverse dose-response relationship between exercise volume and mortality (Arem et al., 2015) suggests volume plays a critical role in mediating the health benefits associated with physical activity, but unfortunately the specific dose of exercise was unavailable in this retrospective cohort. Ultimately, whether the benefits of MICT can be achieved through low volume HIIT is unclear, and worthy of greater scrutiny. Prolonged efforts of low-moderate intensity training (40–70% HRR; in silico modeling to examine optimal metabolic pathways for ATP synthesis (Nilsson et al., 2019). They discovered that beyond ~40% VO₂max, mitochondrial energy flux utilizes the glycerol-phosphate shuttle (Green, 1936; Mráček et al., 2013) to transport electrons directly to ubiquinone and entering at complex III, effectively bypassing complex I to avoid to “backpressure” of the complex I proton pump (Nilsson et al., 2019; Glancy et al., 2020). Notably, this is nearly the same workload where Vollestad reported that type II fibers recruitment begins (Vøllestad and Blom, 1985), which are less reliant on oxidative energy production and have greater state 3 respiration with glycerophosphate as a substrate (Willis and Jackman, 1994). While this model rested on various assumptions, it was consistent with world record running speeds and human data, in which the model was unable to match human gas exchange without complex I bypass....