On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis.
On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis.
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DOI：
10.1016/j.freeradbiomed.2020.10.026
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发表时间：
2020-12
影响因子：
7.4
通讯作者：
Jackson MJ
中科院分区：
文献类型：
--
作者：
Jackson MJ
适当的运动对维持骨骼肌质量和功能至关重要，在任何年龄，特别是在衰老过程中。本文提出了一种假设，认为骨骼肌在衰老过程中无法对运动做出有效反应的一个关键因素是去神经支配诱导的肌肉氧化还原信号失效。这一新的假设提出，肌肉线粒体氧化的初始增加导致肌肉胞浆中信号蛋白的特定半胱氨酸还原状态的矛盾增加，从而抑制了它们在运动过程中对正常氧化氧化还原信号的反应能力。外周运动神经元完整性的短暂性丧失在一生中反复发生，通常通过神经再生迅速修复，但随着年龄的增长，这种修复过程变得不那么有效。神经肌肉完整性的每一次短暂丧失都会导致去神经支配肌纤维和邻近肌纤维中线粒体过氧化物的快速、大量增加。这种过氧化物最初可能刺激轴突发芽和再生，但也刺激逆行有丝核通讯，以增加一系列细胞保护蛋白的表达，以保护纤维和邻近组织免受氧化损伤。线粒体内过氧化物的增加不会导致细胞质过氧化物的增加，但适应性细胞保护蛋白的增加，包括一些位于肌肉细胞质的蛋白质，它们改变了局部细胞质氧化还原环境，诱导特定信号蛋白的关键半胱氨酸的还原状态。骨骼肌对运动的关键适应涉及细胞溶胶中氧化还原信号的瞬时过氧化物还原素氧化效应。这需要对关键的半胱氨酸残基进行敏感的氧化。在衰老过程中，向还原性更强的细胞质环境的慢性变化阻止了过氧化物还氧蛋白2的短暂氧化，从而阻止了对运动的基本适应，从而导致肌肉质量和功能的丧失。本文还概述了适用于检验该假设的实验方法。据推测，在衰老过程中，去神经支配导致氧化还原信号传导失败和肌肉运动反应减弱。外周运动神经元的丧失导致去神经支配和邻近肌纤维中线粒体过氧化物的增加。这种过氧化物刺激细胞保护蛋白的表达，以保护纤维免受氧化损伤。增加的线粒体过氧化物不会增加胞质过氧化物，但适应性降低了胞质氧化还原状态。骨骼肌对运动的关键适应涉及细胞质中瞬时过氧还蛋白氧化。在衰老过程中，过氧还蛋白的氧化被抑制，这是一种向更还原的局部细胞质环境的慢性变化。
Responding appropriately to exercise is essential to maintenance of skeletal muscle mass and function at all ages and particularly during aging. Here, a hypothesis is presented that a key component of the inability of skeletal muscle to respond effectively to exercise in aging is a denervation-induced failure of muscle redox signalling. This novel hypothesis proposes that an initial increase in oxidation in muscle mitochondria leads to a paradoxical increase in the reductive state of specific cysteines of signalling proteins in the muscle cytosol that suppresses their ability to respond to normal oxidising redox signals during exercise. The following are presented for consideration:Transient loss of integrity of peripheral motor neurons occurs repeatedly throughout life and is normally rapidly repaired by reinnervation, but this repair process becomes less efficient with aging. Each transient loss of neuromuscular integrity leads to a rapid, large increase in mitochondrial peroxide production in the denervated muscle fibers and in neighbouring muscle fibers. This peroxide may initially act to stimulate axonal sprouting and regeneration, but also stimulates retrograde mitonuclear communication to increase expression of a range of cytoprotective proteins in an attempt to protect the fiber and neighbouring tissues against oxidative damage. The increased peroxide within mitochondria does not lead to an increased cytosolic peroxide, but the increases in adaptive cytoprotective proteins include some located to the muscle cytosol which modify the local cytosol redox environment to induce a more reductive state in key cysteines of specific signalling proteins. Key adaptations of skeletal muscle to exercise involve transient peroxiredoxin oxidation as effectors of redox signalling in the cytosol. This requires sensitive oxidation of key cysteine residues. In aging, the chronic change to a more reductive cytosolic environment prevents the transient oxidation of peroxiredoxin 2 and hence prevents essential adaptations to exercise, thus contributing to loss of muscle mass and function. Experimental approaches suitable for testing the hypothesis are also outlined. It is hypothesised that denervation leads to failed redox signalling and attenuated muscle exercise responses in aging. Loss of peripheral motor neurons leads to increased mitochondrial peroxide in denervated and neighbouring muscle fibers. This peroxide stimulates increased expression of cytoprotective proteins to protect the fiber against oxidative damage. Increased mitochondrial peroxide does not increase cytosolic peroxide, but adaptations reduce the cytosol redox state. Key adaptations of skeletal muscle to exercise involve transient peroxiredoxin oxidation in the cytosol. Peroxiredoxin oxidation is suppressed during aging by a chronic change to a more reductive local cytosolic environment.
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