Search

Thyroid hormones (TH) are known to control development, body and muscle growth, as well as to determine muscle phenotype in the adult. TH affect muscle properties through nuclear receptors; they act either by a positive or a negative control on target genes that encode proteins accounting for contractile or metabolic phenotypes. Contractile activity and muscle load also affect muscle phenotype; several intracellular signaling pathways are involved in the transduction of signals related to contractile activity, including the calcineurin/NFAT pathway. Calcineurin activity is negatively controlled by MCIP-1 protein (modulatory calcineurin-interacting protein-1). We recently performed an experiment aimed at examining the specific and combined effects of the pharmacological calcineurin inhibition (using cyclosporin-A CsA administration) and thyroid hormone deficiency. The expected effects of CsA administration were only observed if TH were available, while thyroid deficiency totally blunted the muscle responses to calcineurin inhibition. In conditions of thyroid hormone deficiency, there was no response to the pharmacological inhibition of calcineurin, usually known to induce a slow-to-fast IIA transition associated with an enhancement of mitochondrial biogenesis in normothyroid rats. Moreover, thyroid deficiency markedly decreased the expression of MCIP-1 and MCIP-2 mRNA and proteins, two endogenous calcineurin inhibitors; such results clearly suggest that thyroid hormone and calcineurin pathways are interconnected.

Cellular homeostasis requires permanent energy production and consumption. Adenosine triphosphate (ATP) is the major energy component for the cell. Its synthesis occurs mainly in mitochondria where the oxidative phosphorylations realise the coupling between oxygen consumption and phosphorylation of adenosine diphosphate. The anaerobic production of ATP plays an important role in the intermediary metabolism. The enzymatic complexes of the mitochondrial respiratory chain are energy transducers acting as proton pumps. In cardiomyocytes, the phosphocreatine circuit allows a substrate channelling between mitochondria and myofibrils. This metabolic compartmentation explains the difficulties of studying energetic metabolism in the beating heart and the lack of correlation between cardiac function and the usual energy parameters. Mitochondria are a potential site of action of anaesthetic agents. Lipophilic local anaesthetics impair cellular energy metabolism and mitochondrial ATP production. Such effects could be associated with toxic effects of these molecules. NMR or near-infrared spectroscopy are non invasive techniques for monitoring energetic metabolism in vivo. Clinical applications are developed for analysing brain, muscle or cardiac function in physiological and pathological conditions.

Due to glycolysis, anaerobic ATP supports normal electrical activity and allows only a reduced but sustained mechanical activity; however, frog myocardium metabolism is mainly aerobic dependent. Krebs cycle provides ATP for both mechanical and electrical acitivites even when glycolysis is inhibited. The close correlation between amplitude of contraction and metabolic state suggests that ATP is a limiting factor of mechanical activity even in normal conditions. Therefore it is necessary to use oxygen and to add pyruvate which partly compensate for the decrease of mechanical activity observed during the occurrence of hypodynamic state. Moreover equilibrating the oncotic pressure prevents hypodynamia and considerably improves the experimental conditions.

The importance of respecting the ionic equilibrium of cardioplegic solutions was studied experimentally in rat papillary muscle by observing the mechanical and metabolic changes after altering the ionic composition of the washing fluid. The first part of the study demonstrated the nature of the "rigor" of sustained tension induced by the inhibition of the respiratory activity of the mitochondria: this observation showed that this tension was essentially related to the energy deficit induced by poisoning. In the second part, it was shown that calcium overload induced by changing the ionic composition of the nutrient fluid (replacing some of the Na+ ions by K+ or Li+), that is to say related to dysfunction of the Na+-Ca++ exchange induced a contraction which also rapidly evolved to a tension of rigor. This effect was accompanied by a significant reduction in the adenosine triphosphate (ATP) and creatine phosphate (CP) content. The mechanical consequences of prolonged hypoxia or calcium overload are directly related to the reduction in energy reserves producing a marked deficit of ATP in the myofibrils, and resulting in a stable but reversible increase in cardiac muscle rigidity (or rigor). The prevention of calcium overload during the use of cardioplegic solutions is discussed in the context of metabolic myocardial protection. The inhibitory substances of calcium influx such as the calcium antagonist drugs or Mg++ may have an important role to play, in addition to the maintenance of ionic concentrations, especially that of sodium, close to those of the external fluid.