Decreased Mitochondrial Bioenergetics and Function Define a Distinct Metabolic Phenotype in Healthy Sedentary Individuals Detectable Through Non-Invasive CPET

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 60%, p 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