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With increasing energetic demand, both the oxidation of lipids and carbohydrates are rapidly upregulated to generate adenosine triphosphate (ATP), however, at higher exercise intensities (above ~60% VO2 max), there is a relative shift towards carbohydrates as the preferred substrate. Among many factors, a reduction in intramuscular pH which occurs at high exercise intensities has been proposed to contribute to this phenomenon, since the activity of carnitine palmitoyltransferase-I (CPT-I) (the rate limiting enzyme for lipid oxidation) is significantly attenuated in acidic buffers in vitro. To further investigate how pH may influence mitochondrial metabolism, we utilized high-resolution respirometry (HRR) to examine respiratory kinetics with not only lipids, but also carbohydrate- and tricarboxylic acid (TCA) cycle-linked substrates in isolated mitochondria from murine skeletal muscle. While pH did not influence indices of coupling efficiency, a lower buffer pH (pH 6.8 vs 7.2) exerted a generally ubiquitous effect to attenuate both maximal and submaximal respiration supported by equal concentrations of CPT-I substrates (palmitoyl-CoA (P-CoA, trend), L-carnitine (LC)), pyruvate, lactate, glutamate, and succinate while enhancing the ability of malonyl-CoA (M-CoA) to inhibit CPT-I. While these findings may suggest that pH is not a key regulator of fuel shifts in the context of exercise intensity (attenuated both lipid and carbohydrate metabolism), due to the potentially additive effect of attenuated respiration with CPT-I substrates and enhanced CPT-I inhibition with M-CoA, a reduction in pH may contribute to fuel shifts in vivo through greater reductions in lipid oxidation. Additionally, these findings highlight the importance of considering pH effects when designing in vitro experiments with the goal of modelling high intensity exercise. 2023-07-29 |
