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

Abstract

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 O2 differences and 31P 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°C and respiratory chamber oxygen concentrations of ~250 to 500 μmol/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°C higher than skeletal muscle temperatures at maximal exercise (~50°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.

Short-term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes

“…We here presented the two groups together and thereby we are lacking an appropriate control group not being subjected to the intervention. The mitochondrial respiratory measurements in this study are somewhat lower (~33%) than expected in a population with a VO 2max of 65 ml • kg -1 • min -1 [69]. The reason for this is unknown but could be related to lower degrees of mechanical permeabilization during the dissection of the muscle bundles.…”

Under the Hood: Skeletal Muscle Determinants of Endurance Performance

“…Even though the enzyme is not rate limiting for the flux through the Krebs cycle (Blomstrand et al, 1997 ), SDH activity has shown to be proportional to the ex vivo O 2max of intact single muscle fibers and myocardial trabeculas in hyperoxia (van der Laarse et al, 1989 ; Des Tombe et al, 2002 ). Interestingly, both OXPHOS and SDH activity have also shown to be closely related to the O 2max of quadriceps muscles during one-legged exercise (Blomstrand et al, 1997 ; Jacobs and Lundby, 2021 ) and to body-mass-specific O 2max in humans (Costill et al, 1976 ; van der Zwaard et al, 2016a ; Jacobs and Lundby, 2021 ). Recent observations in 68 cardiac patients, controls and elite cyclists demonstrated that mitochondrial oxidative capacity determined from SDH activity even scales proportionally with body-mass-specific O 2max during cycling, ranging 9.8–79.0 mL·kg −1 ·min −1 (van der Zwaard et al, 2016a ).…”

Computational Modeling and Imaging of the Intracellular Oxygen Gradient

“…Notably, these values exceed the greatest values estimated or measured for mammalian mitochondria by an order of magnitude. Simulations were also run with upper limit measured values from high-resolution respirometry of isolated mitochondria/muscle tissue and full body respiratory measurements, of which the latter exceed the former by a factor of three [ 53 , 54 ]. Simulations were performed with these extreme values for maximal consumption rate in order to determine the steepest gradients plausible.…”