Faster O₂ uptake kinetics in canine skeletal muscle in situ after acute creatine kinase inhibition

Non-technical summary: The ability to sustain skeletal muscle contractions is dependent on the conversion of chemical to mechanical energy - a process fueled by adenosine triphosphate (ATP). The link between two of the major mechanisms for ATP provision, phosphocreatine (PCr) breakdown and oxidative phosphorylation, was investigated in canine muscle. Infusion of a drug to prevent PCr breakdown (via inhibition of the enzyme creatine kinase; CK) caused (among other effects) a faster adjustment of energy provision from oxidation upon the onset of contractions. Thus, in mammalian skeletal muscle the CK enzyme slows the signal responsible for the activation of oxidative phosphorylation. Sudden increases in the demands for energy at the onset of exercise are met by PCr breakdown, but this process is functionally related, presumably through the levels of some of its metabolites, to the regulation of oxidative phosphorylation, the most important pathway for ATP resynthesis.Creatine kinase (CK) plays a key role both in energy provision and in signal transduction for the increase in skeletal muscle O₂ uptake at exercise onset. The effects of acute CK inhibition by iodoacetamide (IA; 5 mm) on kinetics were studied in isolated canine gastrocnemius muscles in situ (n= 6) during transitions from rest to 3 min of electrically stimulated contractions eliciting -70% of muscle peak, and were compared to control (Ctrl) conditions. In both IA and Ctrl muscles were pump-perfused with constantly elevated blood flows. Arterial and venous [O₂] were determined at rest and every 5-7 s during contractions. was calculated by Fick's principle. Muscle biopsies were obtained at rest and after -3 min of contractions. Muscle force was measured continuously. There was no fatigue in Ctrl (final force/initial force (fatigue index, FI) = 0.97 ± 0.06 (x±s.d.)), whereas in IA force was significantly lower during the first contractions, slightly recovered at 15-20 s and then decreased (FI 0.67 ± 0.17). [Phosphocreatine] was not different in the two conditions at rest, and decreased during contractions in Ctrl, but not in IA. at 3 min was lower in IA (4.7 ± 2.9 ml 100 g^-1 min^-1) vs. Ctrl (16.6 ± 2.5 ml 100 g^-1 min^-1). The time constant (τ) of kinetics was faster in IA (8.1 ± 4.8 s) vs. Ctrl (16.6 ± 2.6 s). A second control condition (Ctrl-Mod) was produced by modelling a response that accounted for the 'non-square' force profile in IA, which by itself could have influenced kinetics. However, τ in IA was faster than in Ctrl-Mod (13.8 ± 2.8 s). The faster kinetics due to IA suggest that in mammalian skeletal muscle in situ, following contractions onset, temporal energy buffering by CK slows the kinetics of signal transduction for the activation of oxidative phosphorylation.