BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.
BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.
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DOI：
10.1161/circulationaha.116.024873
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发表时间：
2017-07-18
期刊：
影响因子：
37.8
通讯作者：
Kontos CD
中科院分区：
文献类型：
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作者：
McClung JM;McCord TJ;Ryan TE;Schmidt CA;Green TD;Southerland KW;Reinardy JL;Mueller SB;Venkatraman TN;Lascola CD;Keum S;Marchuk DA;Spangenburg EE;Dokun A;Annex BH;Kontos CD
严重肢体缺血（CLI）是外周动脉疾病（PAD）的一种表现，在人类中具有显著的死亡率和发病率风险，尽管其遗传决定因素在很大程度上仍然未知。我们先前在小鼠中发现了两个重叠的数量性状位点（QTL），Lsq-1和Civq-1，分别影响股动脉或大脑中动脉结扎后的肢体肌肉存活率和每搏输出量。在这里，我们报告说，Bag 3变异体（Ile 81 Met）分离与组织保护后肢缺血（HLI）。我们用编码对照（GFP）的腺相关病毒（AAV）或两种BAG 3变体（即Met 81或Ile 81）处理小鼠，并使小鼠后肢缺血。我们发现，在C57 BL/6（BL 6）小鼠背景中的BAG 3 Ile 81 Met变体分离，在Lsq-1（C.B6-Lsq 1 -3）的较短同源片段中具有防止组织坏死的保护作用。与表达Met 81-（n =25）或GFP-（n= 29）的动物相比，用编码BL 6 BAG 3变体（Ile 81）的AAV处理BALB/c小鼠（n = 25）显示肢体组织坏死减少和肢体组织灌注增加。BAG 3 Ile 81，而不是BAG 3 Met 81，改善了缺血性肌肉肌病和肌肉前体细胞分化，并在单独的毒素诱导的损伤模型中改善了肌肉再生。全身注射AAV-BAG 3 Ile 81（n=9），而不是BAG 3 Met 81（n=10）或GFP（n=5），改善了缺血性肢体血流、肢体肌肉组织学，并恢复了肌肉功能（力产生）。与BAG 3 Met 81相比，BAG 3 Ile 81在缺血骨骼肌细胞中表现出改善的与小热休克蛋白（HspB 8）的结合，并增强缺血肌肉自噬通量。总之，我们的数据表明，BAG 3的遗传变异在预防缺血性组织坏死中起着重要作用。这些结果突出了在缺血环境中保护组织存活和肌肉功能的途径。
Critical limb ischemia (CLI) is a manifestation of peripheral artery disease (PAD) that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered two overlapping quantitative trait loci (QTL) in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume following femoral artery or middle cerebral artery ligation, respectively. Here we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hindlimb ischemia (HLI). We treated mice with either adeno-associated viruses (AAV) encoding a control (GFP), or two BAG3 variants, namely Met81 or Ile81, and subjected the mice to hindlimb ischemia. We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). Treating BALB/c mice with AAV encoding the BL6 BAG3 variant (Ile81) (n=25) displayed reduced limb tissue necrosis and increased limb tissue perfusion compared to Met81- (n=25) or GFP- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of AAV-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or GFP (n=5), improved ischemic limb blood flow, limb muscle histology, and restored muscle function (force production). Compared to BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.