Mechanisms of fatigue pre-conditionning (FPC)

肌肉疲劳的定义是骨骼肌力量或工作的减少，当他们被反复刺激。力或功减少的主要机制是肌浆网（SR）释放的Ca 2+量减少，导致肌节的次最大激活。较低的Ca 2+释放降低了肌节激活的程度，并且这两种事件都降低了Ca 2 + ATP酶泵和肌球蛋白ATP酶对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破坏性ATP耗竭。Ca 2+释放减少的一种机制是KATP通道的激活，其在任何代谢应激期间被激活，导致ATP水平降低。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，这进一步支持疲劳是一种肌保护机制的观点。 疲劳预处理（FPC）是一种现象，其中第一次疲劳回合（FAT 1）急剧增加了抗疲劳性，因此在第二次疲劳回合（FAT 2）期间强直性[Ca 2 +]i和力的降低要慢得多。根据FAT 1期间强直性[Ca 2 +]i如何降低，单个FDB纤维可分为三大类，因为FDB肌肉由I型、IIA型和IIX型纤维组成。然而，一旦FPC被触发，所有光纤在FAT 2期间都变得抗疲劳。此外，一旦FPC被触发，KATP通道活性的缺乏不再导致FAT 2期间的收缩功能障碍。如果肌纤维在FAT 2期间不再依赖KATP通道，则可以表明ATP水平得到更好的维持，特别是在疲劳的第1分钟期间，ATP水平在FAT 1期间可以降低40-60%。 假设和假设。所以，问题是i）在FAT 2期间导致更大ATP产生的机制是什么？和ii）FPC中涉及的细胞内信号通路是什么？长期目标仍然是了解肌肉疲劳机制。AMPK是一种细胞能量传感器，调节骨骼肌中葡萄糖摄取、糖原含量和线粒体活性。腺苷是在代谢应激时产生的。它还调节肌肉中的葡萄糖摄取、糖原含量和糖酵解通量。因此，短期目标是测试“FPC由AMPK和腺苷触发，增加肌肉能力以在FAT 2期间更好地产生ATP”的假设。提出了四个目标。目标1：显示了在FAT 2期间通过更大的葡萄糖摄取、糖原动员和更大的线粒体丙酮酸氧化而比FAT 1产生更多的ATP。目标二：证实在FAT 2期间KATP和ClC-1 Cl-通道激活的水平比FAT 1期间低得多，这将进一步证明在FAT 2期间代谢应激比在FAT 1期间低得多。目的3：表明AMPK在触发FPC中至关重要。目的4：表明腺苷在触发FPC中是至关重要的。

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.