Contextualizing the biological relevance of standardized high-resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle

Aim: This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high-resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial-venous O-2 differences and P-31 magnetic resonance spectroscopy (in vivo) and attempt to resolve differences across complementary methodologies as necessary. Methods: Data derived from 831 study participants across research published throughout March 2009 to November 2019 were amassed to examine the biological relevance of ex vivo assessments under standard conditions, ie physiological temperatures of 37 degrees C and respiratory chamber oxygen concentrations of similar to 250 to 500 mu mol/L. Results: Standard ex vivo-derived measures are lower (Z >= 3.01, P <= .0258) en masse than corresponding in vivo-derived values. Correcting respiratory values to account for mitochondrial temperatures 10 degrees C higher than skeletal muscle temperatures at maximal exercise (similar to 50 degrees C): (i) transforms data to resemble (Z <= 0.8, P > .9999) analogous yet context-specific in vivo measures, eg data collected during maximal 1-leg knee extension exercise; and (ii) supports the position that maximal skeletal muscle respiratory rates exceed (Z >= 13.2, P < .0001) those achieved during maximal whole-body exercise, e.g. maximal cycling efforts. Conclusion: This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility and bioenergetics from standard ex vivo-derived assessments using permeabilized human muscle. These findings detail how cross-procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan.

Automated summary

This study aimed to compare measures of mitochondrial function obtained from ex vivo and in vivo assessments, finding that ex vivo measures are generally lower but become more similar after correcting for respiratory data. The results support the idea that maximal skeletal muscle respiratory rates exceed those achieved during maximal whole-body exercise.