1609-P: Whole-Body Metabolic Flexibility Is Discordant with Skeletal Muscle Metabolism

Introduction & Objective: Metabolic inflexibility is the inability to appropriately switch substrate use in response to a metabolic challenge and is seen in individuals with metabolic disease. Metabolic inflexibility can be observed in seemingly healthy individuals, potentially predisposing them to metabolic disease. The goal of this study was to examine if whole-body metabolic inflexibility is reflected by differential substrate use at the skeletal muscle (SkM) level.

Methods: This study recruited young (27 ± 8 years) healthy individuals with overweight. Anthropometric measures, VO₂max test, hyperinsulinemic-euglycemic clamp, and a vastus lateralis biopsy was performed. Based on difference in the respiratory quotient (ΔRQ) during the clamp, participants were median stratified to a “metabolically flexible” (FLEX) (ΔRQ>0.06; n=10) or “metabolically inflexible” (INFLEX) (ΔRQ<0.06; n=9) group. SkM biopsy samples were assessed for substrate oxidation with ¹⁴C-pyruvate and ¹⁴C-palmitate, mitochondrial respiration, and muscle fiber type. Data was analyzed with descriptive statistics, Mann-Whitney U-test, and Student’s t-test.

Results: FLEX had a lower BMI than INFLEX (26.4 ± 1.3 vs 28.7 ± 1.5 kg/m²; p=0.002) but had a similar percentage of body fat (p=0.3) or lean mass (p=0.2). Groups did not differ in age (p=0.06), VO₂max (p=0.3), M value (p=0.1), or basal RQ (p=0.5). FLEX had lower palmitate oxidation than INFLEX (p=0.03) and trended towards a higher ratio of pyruvate to palmitate oxidation (p=0.06). Incomplete palmitate oxidation was also higher in FLEX (p=0.003). Groups did not differ in mitochondrial respiratory capacity (p=0.3) or fiber type (p=0.9). ΔRQ was significantly associated with the M value (p=0.02, r=0.55) and did not associate with fiber type (p=0.6, r=0.16).

Conclusions: FLEX and INFLEX individuals differ in substrate oxidation in SkM tissue with INFLEX showing greater and more efficient fat oxidation. Differences in ΔRQ are not influenced by muscle fiber type.