Mechanisms of fatigue pre-conditionning (FPC)

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Muscle fatigue is defined as a decrease in skeletal muscle force or work when they are repetitively stimulated. The primary mechanism for the decrease in force or work is a decrease in the amount of Ca2+ released by the sarcoplasmic reticulum (SR) resulting in sub-maximal activation of the sarcomere. Lower Ca2+ release reduces the extent of the sarcomere activation, and both events reduce ATP demand by Ca2+ ATPase pumps and myosin ATPase, preserving ATP. This is why fatigue is considered a myoprotective mechanism by which muscles protect themselves from damaging ATP depletion during an activity leading to metabolic stress. One mechanism for the decreased Ca2+ release is an activation of KATP channels, which is activated during any metabolic stress leading to decreased ATP level. KATP channel deficient muscles suffer of severe fiber damage, contractile and metabolic dysfunctions, which further support the notion that fatigue is a myoprotective mechanism. Fatigue pre-conditioning (FPC) is a phenomenon in which a 1st fatigue bout (FAT1) acutely increases the fatigue resistance so that the decreases in tetanic [Ca2+]i and force are much slower during a 2nd fatigue bout (FAT2). Single FDB fibers can be divided into three major groups according to how tetanic [Ca2+]i decreases during FAT1, as FDB muscles is composed of type I, IIA and IIX fibers. Once FPC has been triggered, however, all fibers become fatigue resistant during FAT2. Furthermore, once FPC is triggered, the absence of KATP channel activity no longer causes contractile dysfunctions during FAT2. If muscle fibers no longer rely on KATP channels during FAT2, it can then be suggested that ATP levels are better maintained, especially during the 1st min of fatigue for which ATP levels can decrease by 40-60% during FAT1 OBJECTIVES AND HYPOTHESES. So, the questions are i) what are the mechanisms leading to greater ATP production during FAT2? and ii) what are the intracellular signaling pathways involved in FPC? The long term objective remains the understanding of muscle fatigue mechanisms. AMPK, a cellular energy sensor, modulates glucose uptake, glycogen content and mitochondrial activity in skeletal muscle. Adenosine is produced during metabolic stress. It also modualtes glucose uptake, glycogen content and glycolytic flux in muscle. So, the short term objective is to test the hypothesis that "FPC is triggered by AMPK and adenosine, increasing muscle capacity to better generate ATP during FAT2". Four aims are proposed. Aim 1: show that more ATP is generated during FAT2 than FAT1 via greater glucose uptake, glycogen mobilization and greater mitochondrial pyruvate oxidation. Aim 2: confirm that the level of KATP and ClC-1 Cl-channel activation is much less during FAT2 than FAT1, which will be further evidence that the metabolic stress is much lower during FAT2 than during FAT1. Aim 3: show that AMPK is crucial in triggering FPC. Aim 4: show that adenosine is crucial in triggering FPC.