Mechanisms of fatigue pre-conditionning (FPC)

肌肉疲劳的定义是当骨骼肌力或功受到重复刺激时减少。肌力或功减少的主要机制是肌浆网(SR)释放的钙离子减少，导致肌节处于亚最大激活状态。较低的Ca~(2+)释放减少了肌节的激活程度，这两个事件都通过Ca~(2+)-ATPase泵和肌球蛋白-ATPase减少了对ATP的需求，从而保留了ATP。这就是为什么疲劳被认为是一种肌肉保护机制，通过这种机制，肌肉在导致代谢应激的活动中保护自己免受损害ATP的消耗。钙释放减少的一个机制是激活KATP通道，该通道在任何代谢应激时被激活，导致ATP水平下降。KATP通道缺陷的肌肉遭受严重的纤维损伤、收缩和代谢功能障碍，这进一步支持了疲劳是一种心肌保护机制的观点。疲劳预适应(FPC)是指在第二次疲劳(FAT2)中，第一次疲劳(FAT1)能显著提高运动员的疲劳抗力，从而使强直性[Ca~(2+)]i和力量的下降变得缓慢。由于FDB肌由I型、IIA和IIX纤维组成，根据FAT1过程中强直性[Ca~(2+)]i降低的情况，可将单个FDB纤维分为三大类。然而，一旦FPC被触发，所有纤维在FAT2期间都变得耐疲劳。此外，一旦FPC被触发，KATP通道活动的缺失不再导致FAT2期间的收缩功能障碍。如果肌肉纤维在FAT2期间不再依赖KATP通道，那么可以建议更好地保持ATP水平，特别是在疲劳的第一分钟，在FAT1的目标和假设期间，ATP水平可以下降40%-60%。因此，问题是i)是什么机制导致在FAT2期间产生更多的ATP？以及ii)FPC中涉及的细胞内信号通路是什么？长期的目标仍然是了解肌肉疲劳的机制。AMPK是一种细胞能量感受器，调节骨骼肌的葡萄糖摄取、糖原含量和线粒体活性。腺苷是在新陈代谢压力下产生的。它还可以调节肌肉中的葡萄糖摄取、糖原含量和糖酵解通量。因此，短期目标是验证这一假设，即“FPC是由AMPK和腺苷触发的，在FAT2期间增加肌肉能力以更好地产生ATP”。提出了四个目标。目的1：证明FAT2比FAT1通过更多的葡萄糖摄取、糖原动员和线粒体丙酮酸氧化而产生更多的ATP。目的：证实FAT2时KATP和ClC-1Cl-通道激活水平明显低于FAT1，进一步证明FAT2时代谢应激程度明显低于FAT1时。目的3：证明AMPK在触发FPC中起关键作用。目的4：证明腺苷在FPC的触发中起关键作用。

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.