High-resolution respirometry (HRR)-derived assessment of human skeletal muscle respiratory control confirms loss of metabolic flexibility with aging and type 2 diabetes

Abstract

Compromised metabolic flexibility is linked to skeletal muscle respiratory control limitations and associated with human senescence and pathological conditions, like type 2 diabetes mellitus (T2D). However, demonstrable proof of compromised metabolic flexibility is limited in research studying aging and T2D, possibly because respiratory control per consensus is commonly assessed at 37°C when mitochondrial temperatures have been shown to reach ~50°C. Therefore, the study objective was to assess indices of skeletal muscle respiratory control and metabolic flexibility via high-resolution respirometry (HRR) in older individuals (OFM) and those diagnosed with T2D. Our hypothesis is that both populations, OFM and T2D, will present with diminished metabolic flexibility when compared to relative controls, young fitness-matched (YFM) or body-mass and BMI-matched middle-aged overweight or obese (MAOO) controls, respectively. Study methodology involved: i) Collecting published HRR-derived assessments of skeletal muscle state 3 respiration using complex I+II substrates obtained with standard experimental conditions at 37°C (OXPHOS 37 ); ii) Temperature correcting published values to reflect mitochondrial temperatures ~10°C higher than contracting muscle (OXPHOS ~50 ); and iii) Estimating metabolic flexibility by taking the difference of OXPHOS 37 from OXPHOS ~50 . Data show that OFM (n = 170; age = 65 ± 6 y; Fitness Percentile = 48 ± 29%) express higher (p < 0.001) rates of OXPHOS 37 than YFM (n = 154; age = 25 ± 5 y; Fitness Percentile = 43 ± 14%) with average rates of 123 ± 39 and 109 ± 31 ml/kg/min, respectively, but no observable difference (p = 0.113) between T2D (n=148, body mass = 99 ± 17 kg, BMI = 32 ± 5) and MAOO (n = 267, body mass = 97 ± 19 kg, BMI = 32 ± 6) with average rates of 96 ± 24 and 100 ± 25 ml/kg/min, respectively. Alternatively, temperature correction and determination of metabolic flexibility confirmed our study hypothesis in OFM v YFM (5.88 ± 1.57 and 6.32 ± 1.92 l/min, respectively, p = 0.026) as well as T2D v MAOO (115 ± 29 and 122 ± 31 ml/kg/min, respectively, p = 0.024). A summary of results confirms that OFM and T2D suffer from compromised metabolic flexibility. However, these findings were only observable after temperature correcting previously published HRR-derived data. Conclusions: This study further highlights the importance of maintaining muscle mass and relative fitness, respectively, to retain metabolic flexibility throughout life. Also, general standardized HRR methodologies may currently obscure some biological context and, thus, limit our full application of related research. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.