Temporal analysis of skeletal muscle remodeling post hindlimb ischemia reveals intricate autophagy regulation.
Temporal analysis of skeletal muscle remodeling post hindlimb ischemia reveals intricate autophagy regulation.
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DOI：
10.1152/ajpcell.00174.2022
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发表时间：
2022-12-01
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后肢缺血（HLI）是外周动脉疾病的最严重形式，与肢体血流量的大幅减少有关，这损害了骨骼肌的稳态，从而促进功能障碍。HLI诱导的肌肉扰动的分子调节剂仍然不清楚。本研究探讨了分子分解代谢-自噬信号网络的变化是否与HLI中骨骼肌的时间重构有关。通过后肢缺血（股动脉结扎）在小鼠中诱导HLI，并通过多普勒超声心动图证实。实验在定义为早期（7天; n = 5）或晚期（28天; n = 5）HLI的时间点终止。比较缺血和非缺血（对侧）肢体肌肉。缺血性与非缺血性肌肉表现出明显的重塑在早期HLI，但在晚期HLI正常化。早发性纤维萎缩与缺血肌肉中过度的自噬信号有关; Beclin-1、LC 3和p62的蛋白表达增加（P < 0.05），但蛋白酶体依赖性标志物减少（P < 0.05）。在早期HLI中，线粒体自噬信号增加，这与线粒体含量的早期和持续损失一致（P < 0.05）。上游自噬调节因子Sestrins在早期HLI期间表现出不同的反应（Sestrin 2增加而Sestrin 1减少; P < 0.05），与AMP活化蛋白激酶（AMPK）磷酸化增加（P < 0.05）和抗氧化酶表达降低平行。在雷帕霉素复合物1信号传导的机制靶标的标记物中没有发现变化。这些数据表明，sestrin-AMPK信号轴的早期激活可调节自噬以刺激HLI中的快速和明显的肌肉萎缩，其在数周内正常化并伴随肌肉质量的恢复。在HLI的早期至晚期肌肉重塑期间，Sestrin之间可能存在复杂的相互作用以调节自噬信号传导。
Hind limb ischemia (HLI) is the most severe form of peripheral arterial disease, associated with a substantial reduction of limb blood flow that impairs skeletal muscle homeostasis to promote functional disability. The molecular regulators of HLI-induced muscle perturbations remain poorly defined. This study investigated whether changes in the molecular catabolic-autophagy signaling network were linked to temporal remodeling of skeletal muscle in HLI. HLI was induced in mice via hindlimb ischemia (femoral artery ligation) and confirmed by Doppler echocardiography. Experiments were terminated at time points defined as early- (7 days; n = 5) or late- (28 days; n = 5) stage HLI. Ischemic and nonischemic (contralateral) limb muscles were compared. Ischemic versus nonischemic muscles demonstrated overt remodeling at early-HLI but normalized at late-HLI. Early-onset fiber atrophy was associated with excessive autophagy signaling in ischemic muscle; protein expression increased for Beclin-1, LC3, and p62 (P < 0.05) but proteasome-dependent markers were reduced (P < 0.05). Mitophagy signaling increased in early-stage HLI that aligned with an early and sustained loss of mitochondrial content (P < 0.05). Upstream autophagy regulators, Sestrins, showed divergent responses during early-stage HLI (Sestrin2 increased while Sestrin1 decreased; P < 0.05) in parallel to increased AMP-activated protein kinase (AMPK) phosphorylation (P < 0.05) and lower antioxidant enzyme expression. No changes were found in markers for mechanistic target of rapamycin complex 1 signaling. These data indicate that early activation of the sestrin-AMPK signaling axis may regulate autophagy to stimulate rapid and overt muscle atrophy in HLI, which is normalized within weeks and accompanied by recovery of muscle mass. A complex interplay between Sestrins to regulate autophagy signaling during early-to-late muscle remodeling in HLI is likely.
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