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bioRxiv · 10.1101/2024.08.19.608601

Metabolic and Cellular Differences Between Sedentary and Active Individuals at Rest and During Exercise

San-Millan, I.·Martinez, J.·Sparagna, G.·D'Alessandro, A.·Stefanoni, D.·Nemkov, T.·Hill, J.
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Abstract

BackgroundPhysical inactivity is a major contributor to cardiometabolic disease and mortality. Although mitochondrial dysfunction characterizes overt pathology, whether a distinct mitochondrial phenotype is present in apparently healthy sedentary adults remains unclear. MethodsNine sedentary (SED) and ten physically active (AC) healthy males (42 {+/-} 14 yr) were studied. Skeletal muscle bioenergetics were assessed using high-resolution respirometry, fluxomics, metabolomics and protein expression analyses. Whole-body physiology was evaluated using cardiopulmonary exercise testing (CPET) including fat oxidation and blood lactate measurements. ResultsAt rest, SED exhibited marked reductions in mitochondrial capacity, including Complex I (-36%), Complex II (-28%), electron transport system capacity (-34%), and ATP-synthase-coupled respiration (-30%, all p < 0.01). The most pronounced alteration was a 49% reduction in mitochondrial pyruvate carrier (MPC1) expression, which closely correlated with reduced pyruvate oxidation (-37%, p = 0.006) and lower TCA intermediates. SED also showed reduced MCT1 abundance, impaired fatty acid oxidation capacity (-32% to -35%), decreased CPT1 activity (-51%), altered cardiolipin composition and elevated ROS/O flux ratios. During exercise, SED demonstrated lower VO max (-38%), reduced fat oxidation (-35%) and higher blood lactate accumulation (>60%, p < 0.001). Mitochondrial function was strongly associated with exercise performance (r = 0.57-0.78, p < 0.01). ConclusionsHealthy sedentary adults are characterized by reduced mitochondrial function characterized by decreased substrate entry and oxidation, reduced oxidative capacity and diminished metabolic flexibility. CPET-derived fat oxidation and blood lactate responses closely reflect skeletal muscle mitochondrial function, providing non-invasive physiological markers of metabolic health. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/608601v2_fig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1a3a629org.highwire.dtl.DTLVardef@f1ea48org.highwire.dtl.DTLVardef@4c4a96org.highwire.dtl.DTLVardef@b4f879_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Schematic of skeletal muscle mitochondrion: SED side shows reduced MPC, CPT1, L4CL, and TCA flux with elevated ROS; AC side shows robust OXPHOS, fat oxidation, and lactate clearance. Arrows link to CPET as a non-invasive diagnostic tool for mitochondrial health. C_FIG

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San-Millan, I., Martinez, J., Sparagna, G., D'Alessandro, A., Stefanoni, D., Nemkov, T., Hill, J.. 2024-08-19. Metabolic and Cellular Differences Between Sedentary and Active Individuals at Rest and During Exercise. https://doi.org/10.1101/2024.08.19.608601

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