Metabolic and Cellular Differences Between Sedentary and Active Individuals at Rest and During Exercise
Authors: San-Millan Inigo , Martinez Janel L. , Sparagna Genevieve C. , D’Alessandro Angelo , Stefanoni Davide , Nemkov Travis , Hill John 
Published: August 2024

ABSTRACTLack of physical activity has been associated with multiple diseases including cardiovascular disease (CVD), cancer, Alzheimer’s disease (AD), type 2 diabetes (T2D), Parkinson’s disease, depression, dementia and even cancer. Mitochondrial impairment or dysfunction is associated with lack of physical activity and considered to be involved in the pathogenesis of the most prevalent non-communicable diseases (NCDs) aflicting our societies such as T2D, CVD, metabolic syndrome, and even AD.To our knowledge, there is a scarcity of studies on the metabolic, mitochondrial and cellular characteristics of “healthy sedentary” individuals living without clinical symptoms. Hence, the main aim of our study herein was to characterize multiple metabolic, mitochondrial and cellular bioenergetic signatures in “healthy sedentary” individuals which could already be downregulated compared to moderately active individuals.Nineteen subjects, 9 sedentary (SED) and 10 moderately active (AC) volunteered for multiple assessments including muscle biopsies, in order to assess muscle metabolism, mitochondrial respiration and bioenergetics both at rest and during exercise.For our exercise studies, we performed graded exercise testing (GXT) to assess carbohydrate and fat oxidation capacity as well as lactate clearance capacity according to our previously developed methodology.Resting studies showed decreased mitochondrial respiration including decreases in complex I (-36%) and II (-28%) as well as total electron system capacity (-34%) and electron system capacity coupled to ATP production via ATP synthase (-30%). Regarding muscle carbohydrate metabolism, SED individuals showed a decrease in mitochondrial pyruvate oxidation (-37%) as well as reduced expression (-49%) of mitochondrial pyruvate carrier (MPC). Regarding fatty acid metabolism, SED showed decreased activity of carnitine palmitoyltransferase I (CPT1)(-51%) and CPT2 (-44%) as well as decreased mitochondrial fatty acid oxidation (-35%). Metabolomics analysis also confirmed downregulation of carbohydrate and fat metabolism. Partial Least-Squares Discriminant Analysis (PLS-DA) identified distinct metabolic phenotypes through intermediates of glycolysis and fatty acid oxidation. Further, we found significant differences in cardiolipin (CL) species expression between SED and AC groups, which, due to the important role of CL in mitochondrial structure, function, biogenesis and bioenergetics, deserves further attention.Exercise studies also showed significant differences in substrate utilization between groups where SED possessed a significantly lower fat oxidation capacity as well as lactate clearance capacity. The correlation of different bioenergetic parameters between resting and exercise conditions were robust, suggesting the possibility of performing cardiopulmonary exercise testing (CPET) as a non-invasive methodology to indirectly assess metabolic function in multiple populations. In summary, in our study herein, we show that “healthy sedentary” individuals already possess a significant decrease in cellular metabolism, mitochondrial respiration and bioenergetics compared to moderately active individuals both during resting and exercising conditions.Since large numbers of sedentary individuals evolve to develop cardiometabolic disease, a better understanding of decreased cellular bioenergetics and mitochondrial function is needed in order to improve both diagnosis and treatment of multiple metabolic diseases.Abstract FigureCONCLUSIONS- Sedentary individuals possess significant decreases in mitochondrial respiration as well as muscle bioenergetics during resting conditions compared to moderately active individuals.- Despite similar GLUT-4 concentrations, sedentary individuals show significant decreased pyruvate oxidation as well as expression of mitochondrial pyruvate carrier (MPC).- During exercise studies, sedentary individuals show significantly decreased levels of fat oxidation and lactate clearance capacity which correlate with mitochondrial and bioenergetics parameters from resting muscle biopsies. Hence, cardiopulmonary exercise testing (CPET) accompanied by measuring blood lactate levels could be a practical manner to assess muscle mitochondrial function and bioenergetics in a non-invasive and ambulatory manner.- Identifying early signatures of decreased mitochondrial function and bioenergetics capacity could be an important approach to prevent or improve different metabolic diseases through lifestyle changes mainly from exercise and nutrition.