Submaximal Exercise Testing for Metabolic Flexibility: A Possible Window Into Mitochondrial Function

INTRODUCTION

Over the past 2 decades, the increasing prevalence of metabolic syndrome (MetS) has emerged as a significant global public health issue. Currently, over one third of adults meet the criteria for MetS.¹ However, more concerning is a recent report indicating that <20% of U.S. adults are metabolically healthy.² Metabolic health is defined not only by the absence of MetS but also by optimal levels of traditional MetS markers. This suggests that the onset of metabolic disease may begin to manifest well before the primary components of MetS—namely, obesity, hypertension, dyslipidemia, and insulin resistance—become evident. Consequently, early diagnosis and management are essential for preventing or at least delaying the progression of MetS. One proposed method for the early detection of MetS involves measuring expired gases during submaximal exercise at low-to-moderate intensities.3, 4, 5

METABOLIC FLEXIBILITY

Recent studies have identified mitochondrial dysfunction as a critical factor in the early development of MetS,⁶ and it is associated with various metabolic disorders, including Type 2 diabetes and insulin resistance.^7,8 The mitochondria's primary role is to utilize nutrients to generate energy for cellular activities through the process of cellular respiration. Although the bioenergetics of cellular respiration are intricate, the mitochondria's ability to alternate between energy substrates, primarily fats and carbohydrates (CHOs), to produce adenosine triphosphate and fulfill metabolic demands is termed metabolic flexibility (MF).³ Impaired MF has recently been recognized as the fundamental cause of mitochondrial dysfunction and, consequently, a significant contributor to numerous contemporary metabolic diseases.³ Currently, there is no standardized method for assessing mitochondrial function and MF. Existing methods include evaluating oxidative enzymes from muscle biopsies and/or employing cell cultures, both of which are invasive and impractical for the general population.⁸ Noninvasive techniques involve the use of nuclear magnetic resonance and magnetic resonance spectroscopy; however, this technology is expensive and not feasible for routine application.^7,8 Alternative methods encompass glucose and insulin infusions; dietary challenges; epinephrine infusions; sleep challenges; and more recently, submaximal exercise.9, 10, 11, 12 Exercise presents an optimal challenge to the metabolic environment of skeletal muscle, where the utilization of fat and CHO within the mitochondria varies according to the stress or exercise intensity imposed on the body.⁷

SUBMAXIMAL EXERCISE

The predominant method for evaluating the metabolic response to exercise is indirect calorimetry.³ This technique employs a metabolic cart to quantify the volume and concentration of expired carbon dioxide and oxygen (volume of oxygen [VO2]). Subsequently, fat and CHO oxidations are calculated using a stoichiometric equation to ascertain the point of maximal fat oxidation (MFO).⁹ A higher reliance on CHO oxidation or, conversely, low MFO values at moderate-to-low exercise intensities indicate suboptimal MF. Moreover, data derived from MF assessments provide precise training intensities for individualized training programs aimed at enhancing the health and fitness of both athletic and clinical populations.⁷ Achten and colleagues conducted one of the initial studies examining MF during exercise, investigating fat oxidation with 5-minute, 35-Watt increments during a VO2 max test in trained cyclists.¹⁰ MFO was observed at an average of 64% of VO2 max, with a substantial range of 42%–84%. It was also noted that fat oxidation rates significantly decreased once exercise intensity surpassed the peak MFO point, indicating a shift in substrate utilization from fat to CHO.¹⁰ Since this pioneering study, reported MFO values in the literature have varied considerably, ranging from as low as 20% to as high as 80%.³ This variability may be attributed to several factors influencing fat oxidation during exercise, such as age, training status, sex (female, male), nutritional status, and body composition.⁴ In addition, the implementation of diverse protocols has further complicated the MFO values reported in the literature.¹¹ More recently, San-Millán and Brooks⁵ investigated the MF of elite athletes, sedentary individuals, and clinical populations, incorporating lactate measurements during submaximal exercise. Blood lactate was found to be negatively correlated with fat oxidation, providing further evidence that this test can indirectly assess mitochondrial function and MF across different populations.⁵ Supporting these findings, a recent comparison between invasive and noninvasive markers of mitochondrial function identified exercise efficiency (calculated through indirect calorimetry) as the most effective noninvasive marker of mitochondrial respiratory capacity.⁸

A significant advantage of employing a submaximal exercise test for assessing MF is its requirement for only a low-to-moderate intensity. For the majority of individuals, MFO occurs at or below 50%–60% of VO2 max,^3,12 thereby eliminating the need for maximal effort and motivation, as is necessary in other exercise tests such as the VO2 max test. In addition, the lower intensity reduces the possible risk of adverse events in elderly and other clinical populations. Furthermore, recent evidence utilizing stable isotopes has demonstrated that exercise intensities exceeding 70% of VO2 max may lead to inaccuracies in calculating fat and CHO oxidation from stoichiometric equations.¹² This inaccuracy may arise owing to the increased intensity elevating [H+], which is subsequently buffered by [HCO3-], resulting in the production of excess (nonoxidative) carbon dioxide.¹² Collectively, these findings advocate for the use of a submaximal exercise test to evaluate mitochondrial function and MF. A noninvasive submaximal exercise test, requiring <30 minutes, may suffice to determine MF and metabolic health.⁴

CONCLUSIONS

Further investigation is required to determine the most appropriate protocol for evaluating fat oxidation and MF across diverse populations. It is apparent that even within homogeneous groups, the metabolic response to exercise is highly individualized, necessitating careful comparison with other groups. Nonetheless, despite the current uncertainties, assessing substrate utilization through a submaximal exercise test shows considerable promise as an efficient and relatively noninvasive method for evaluating MF and mitochondrial health.