Oxidative ATP synthesis above the lactate threshold: a sexual dimorphism perspective

Skeletal muscle typically amounts to 40–50% of total body weight of the average human being. In addition, skeletal muscle is a highly plastic organ which adapts to an individual's lifestyle, increasing or decreasing metabolic and physical functions. As one of the largest and most active organs, any adaptation to skeletal muscle form and function can drive whole-body adaptations in health and disease. Chronological ageing and sedentarism impose unique stresses on this metabolic tissue such that it typically decreases in size and function, has increased lipid storage, has decreased insulin sensitivity, and shows an overall decrease in metabolic activity (Distefano & Goodpaster, 2018). These physiological maladaptations contribute to comorbidities such as type 2 diabetes, cardiac disease and all-cause mortality. Cardiovascular fitness is measured by maximal whole-body oxygen uptake (). As skeletal muscle is the most metabolically active tissue, cardiovascular fitness and oxygen uptake are largely dependent on the metabolic health of skeletal muscle. Within the skeletal muscle, the mitochondria are the largest oxygen consumers and ATP producers at rest and during aerobic exercises, typically those performed at low to moderate intensities (i.e. below ∼70% ). When aerobic metabolism is no longer sufficient to support energy demand, lactate production begins to exceed lactate removal, and anaerobic metabolism becomes increasingly recruited to match ATP demand. This is known as the lactate threshold. The lactate threshold tends to occur at lower exercise intensities in untrained individuals and higher exercise intensities with endurance training. In conjunction with various other markers, including maximal oxygen uptake (), the lactate threshold is used to indicate an individual's cardiovascular fitness and aerobic conditioning. Skeletal muscle metabolism above the lactate threshold is associated with acidosis and rates of phosphocreatine breakdown, ADP accumulation and oxygen uptake that are inflated beyond those below the lactate threshold (Bartlett et al. 2021). As discussed in the recent publication in The Journal of Physiology by Bartlett et al. (2021), these conditions appear to be a result of metabolic inefficiencies that tend to accelerate skeletal muscle fatigue, but the metabolic mechanism through which this occurs above the lactate threshold is currently not well defined. It was reported by Cannon and colleagues (2014) that mitochondrial inefficiency may minorly contribute to this phenomenon, while increased ATP cost of contraction played a major role in increasing oxygen consumption as a mechanism leading to skeletal muscle fatigue above the lactate threshold. Alternatively, Barlett et al. suggested that the inflated rates of oxygen consumption observed above the lactate threshold are indeed a result of mitochondrial uncoupling, which impairs mitochondrial uncoupling. Accordingly, the purpose of the study conducted by Bartlett et al. (2021) was to determine the contribution of ATP cost of contraction and mitochondrial ATP production as they relate to mechanisms of metabolic inefficiencies that contribute to the lactate threshold. To measure this, three recreationally active women and five recreationally active men were asked to perform two to three maximal voluntary isometric contractions (MVIC) for 3–5 s followed by two to three sets of maximal voluntary dynamic contractions (MVDC) before completing a six-stage stepwise knee extension test. Stage 1 began at 6–10% of the participant's MVIC and increased by 2% of MVIC every successive stage. Non-invasive 31P magnetic resonance spectroscopy (31P-MRS) was used to determine the production and disappearance of metabolic markers such as ATP, ADP and creatine in real time. Intramyocellular H+ was also measured using 31P-MRS as a surrogate for lactate. Using 31P-MRS, these authors determined that: (1) rates of ATP synthesis are not immediately impaired at high intensity contractions close to but above the lactate threshold, but skeletal muscle oxidative capacity does become impaired at contraction intensities above the lactate threshold, (2) the energetic cost of skeletal muscle contraction does not change with exercise workload above the lactate threshold, (3) the initial rate of phosphocreatine resynthesis increases linearly below the lactate threshold, but plateaus above the lactate threshold regardless of workload, and (4) ADP concentration increases throughout each exercise bout. Thus, in contrast to Cannon et al. (2014), these results suggest that inflated rates of oxygen consumption observed above the lactate threshold are not a result of greater ATP cost, and are instead primarily due to mitochondrial uncoupling at high contraction intensities. Rather, sharp increases of oxygen uptake at the lactate threshold are likely due to mitochondrial uncoupling at high contraction intensities up to 3-min long. As Cannon et al. tested exercise contraction intervals up to 8 min in length, it is possible that the length of time the muscle is contracting contributes to the differences in these studies. Future research should directly compare stepwise contraction protocols that use 3-min stages against those lasting longer, such as 8 min, to resolve this conflicting result. The identification of the metabolic mechanisms underlying the lactate threshold during exercise is critical in understanding the molecular basis of fatigue. With identification of these mechanisms above the lactate threshold, we can identify appropriate pathways and molecular markers to target for the improvement of skeletal muscle efficiency in both healthy athletic and pathological skeletal muscle. Yet, there is still a gap in the literature regarding the influence of sex on metabolism above the lactate threshold. Although not measured in the current study, sex-based differences exist in the use of metabolic fuel during exercise. In 2010, the response of the high energy phosphate system to high intensity contraction, at and above the lactate threshold, was compared in young, healthy men and women (Willcocks et al. 2010). Similar to Bartlett et al., Willcocks et al. (2010) measured phosphates of the quadricep via changes in the 31P spectra using 31P-MRS, but single exercise bouts at or above the lactate threshold lasted 7 min rather than the 3 min of the current study. Willcocks et al. reported lower phosphocreatine and higher in ADP concentrations in females compared to males. However, the men and women were not matched for training status, fat free mass, or making it unclear whether their relative power outputs were physiologically comparable. Regardless, Willcocks et al. have demonstrated that women may have a lesser ability to resynthesize phosphocreatine at high contraction intensities compared to men, which they suggest is a result of impaired oxidative capacity. Taken with the current study, it is possible that women have greater susceptibility to mitochondrial uncoupling than men at higher contraction intensities. Further support for mitochondrial inefficiencies under metabolically stressful environments is provided by Miotto et al. (2018) who compared mitochondrial respiratory capacity between young, recreationally active men and women. Although men and women were not matched for physical fitness, relative fat or fat-free mass, mitochondrial respiration rates and mitochondrial protein content were similar between the sexes (Miotto et al. 2018). As mitochondrial content was matched, any differences are likely due to factors intrinsic to the mitochondria between the sexes. ADP-stimulated mitochondrial respiration was significantly lower in these women than men, identified by a 30% higher apparent Km of mitochondrial flux (Miotto et al. 2018). Despite similar mitochondrial function, women appear to have reduced sensitivity to metabolic stress signals, namely ADP, than men. Importantly, high intensity contractions at and above the lactate threshold support the production of ADP (Bartlett et al. 2021), but women are comparatively less sensitive to ADP than men (Miotto et al. 2018). Therefore, the mitochondrial uncoupling hypothesis suggested by Bartlett et al. may occur in men but, based on our review of the above data in conjunction with the current data, likely not in women. In conclusion, using a sensitive and non-invasive technique which can identify real time changes in high energy phosphates during exercise and at rest, Bartlett et al. (2021) demonstrate that rapid increases in whole-body oxygen uptake at one's lactate threshold is not likely a result of increased ATP cost in recreationally active, healthy, young adults. Rather, augmented whole-body oxygen uptake with sufficient mitochondrial oxidative phosphorylation supports the thesis that mitochondria become increasingly uncoupled above the lactate threshold. This uncoupling effect may contribute to metabolic mismatching at contraction intensities near maximal effort. Additionally, previous research suggests that women might experience different metabolic limitations at and above the lactate threshold, which may be a result of greater sensitivity to mitochondrial uncoupling. It is unclear if these differences are dependent on the of sex hormone concentration throughout the menstruation cycle. This is important as it suggests that women may not respond to exercise and exercise interventions the same way as men resulting in a lack of treatment strategies for women. Future research should build upon this current research through the use of muscle biopsies to directly determine the effect of the lactate threshold on mitochondrial uncoupling and to effectively compare appropriately matched men to women throughout the menstrual cycle. 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. Both authors have no conflicts of interests to declare. J.A.W. and W.S. both contributed equally to the writing of this manuscript. J.A.W. and W.S. both contributed equally to the editing of this manuscript. Both 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. None.

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