Mitochondrial sensitivity to regulatory signals in muscle energy balance: is it constant during exercise?

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The sensitivity of mitochondrial ATP synthesis to regulatory signals elevated by muscle exercise was investigated in a rat model using an integrative approach of physiologic experiments and computer simulation. Time courses of hindlimb muscle phosphocreatine (PCr) and Pi and pH during serial contractions and recovery were recorded using in vivo phosphorus NMR spectroscopy. Muscle contractions were elicited using sciatic nerve pacing over a tenfold range of frequencies (0.25–2 Hz) with concurrent force recording from the Achilles tendon. At each contraction frequency, the mitochondrial ATP synthesis rate was determined from PCr and pH dynamics and correlated with the concentrations of the regulatory metabolites ADP and Pi. Data were analyzed using a computational model of mitochondrial ATP synthesis and accounting for cytosolic fluxes of phosphate buffering and glycolytic pathways. The integrated model was compared to empirical data and used to explore the feasibility of competing hypotheses regarding the control of mitochondrial dehydrogenases and respiratory fluxes.