Figure 5 Time courses of [H+] and [Mg2+] during

extreme power output. A: [H+] fluxes; (brown) mainly LDH reaction and lactate transport; (red) ATP splitting; (blue) JAK; (yellow) JCK; (black line) resultant [H+] flux; B: [Mg2+] fluxes of the same reactions. A second source of protons is given by the disturbance of lactate production by glycogenolysis (or glycolysis) and lactate efflux via lactate/H symport at the sarcolemma. Especially when lactate and H+ accumulate in the glycocalyx (the outer aspect of the sarcolemma), the concentrations of these mTOR inhibitor compounds also increase Inhibitors,research,lifescience,medical drastically in the sarcosol. This seems to be the main mechanism of sarcosolic acidification. Muscular fatigue at the cellular level can be defined as a phase of markedly reduced contractile performance, which largely recovers after a period of rest [38]. Because metabolites like creatine, ADP, Pi, H+, and lactate accumulate during conditions of fatigue in a similar way Inhibitors,research,lifescience,medical as can be observed during ischemia or hypoxia, which are known to be the result of impaired ATP production, it seems justified to suggest that the preconditioning for fatigue may also be initiated by a deterioration of the energy metabolism of the muscle fibers. Whenever ATP delivery does not match ATP consumption, such a situation may arise.

These Inhibitors,research,lifescience,medical effects can be easily demonstrated with a simulation of glycogenolytic or glycolytic ATP production in the absence of mitochondrial metabolism (SIMGLYgen, see (A16)), which is related to the energy metabolism of fast muscle fibers. At 1.08 µM [Ca2+] and a Inhibitors,research,lifescience,medical load of –1.5 × 104 J (constant glycogen content and glucose concentration [Glu] = 4.0 mM), efficiency of glycogenolytic Inhibitors,research,lifescience,medical ATP production is ηGLYgen = 0.722, that of glycolytic ATP ηGLY = 0.525. The higher efficiency is mainly caused by the stoichiometric coefficients of coupled ATP production of 3.0 and 2.0

for the glycogenolytic and glycolytic pathways, respectively. Under these conditions of high power output, metabolite concentrations change only moderately compared to resting conditions (at 1.06 µM [Ca2+] and a load potential of −1.5 × 104 J/mol, [ADP] = 113, [Pi] = 8.32 × 103, phosphocreatine concentration [PCr] = 9.7 × 103, lactate Etomidate concentration [Lac] = 3.0 × 103, [Mg2+] = 832, and pH = 7.09). However, when a back pressure on glycogenolysis (or glycolysis) is produced by accumulated extracellular [Lac]e and [H+]e, the flux through this pathway may become reduced. In addition, efficiency has been reduced by switching from glycogenolysis to glycolysis. The power output of ATP production is markedly reduced by these combined effects. As a result, the power of ATP production begins to fall, so that ATP consumption may overcome ATP production. Steady state cycling through ATP consuming and producing pathways can now no longer be maintained.