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

  1. Iñigo San-MillĂ¡n
  2. Janel L. Martinez
  3. Genevieve C. Sparagna
  4. Angelo D’Alessandro
  5. Davide Stefanoni
  6. Travis Nemkov
  7. John Hill
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Abstract

Background

Physical 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.

Methods

Nine 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.

Results

At 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).

Conclusions

Healthy 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

<fig id="fig1" position="float" orientation="portrait" fig-type="figure"> <label>Figure 1.</label> <caption>

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.

</caption> <graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="608601v2_fig1" position="float" orientation="portrait"/> </fig>

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