Inducible Heat Shock Protein 70 Levels in Patients and the mdx Mouse Affirm Regulation during Skeletal Muscle Regeneration in Muscular Dystrophy.
Inducible Heat Shock Protein 70 Levels in Patients and the mdx Mouse Affirm Regulation during Skeletal Muscle Regeneration in Muscular Dystrophy.
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DOI：
10.31083/j.fbs1403019
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发表时间：
2022-07-15
期刊：
影响因子：
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通讯作者：
De Paepe, Boel
中科院分区：
文献类型：
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作者：
Cosemans, Gwenny;Merckx, Caroline;De Paepe, Boel
背景：应激诱导热休克蛋白70(HSP70)既是参与蛋白质稳态的保护性伴侣，又是免疫调节因子。在这两种情况下，HSP70都与肌肉疾病有关，但结果支离破碎，结果不同。在这项研究中，我们旨在将在相当于Duchenne MD的最严重的肌营养不良(MD)小鼠模型上获得的结果与在人类MD上获得的结果进行比较。方法：来自11名健康对照组、11名完全特征的Becker MD和肢体带MD(LGMD)患者以及6名肌肉疾病对照组。另外，在4、8和12周龄时，分别从MDX和对照组小鼠的胫骨前肌制备肌肉提取物。结果：我们发现MDX胫骨肌中HSP70蛋白的表达仅在疾病的最早阶段有选择性且显著上调2.2倍。在LGMD和Becker MD患者中，HSP70蛋白水平与正常肌肉和血清中的HSP70蛋白水平无显著差异。在小鼠和人MD骨骼肌组织中，HSP70均定位于再生肌纤维。Toll样受体(Toll-like Receptor，TLR)2和TLR4在MD小鼠肌肉膜上的表达呈中度升高，但其蛋白表达水平与正常对照组无显著差异。结论：MD小鼠肌肉组织中HSP70表达的上调与疾病分期有关，标志着MDX小鼠肌肉再生最活跃的时期。我们推测，适时使用HSP70激动剂的支持性治疗干预可能会潜在地改善MD患者肌肉组织的再生能力，在我们等待基因治疗变得更广泛的同时，减轻肌肉质量的损失。
BACKGROUND: Stress-inducible heat shock protein 70 (HSP70) is both a protective chaperone involved in protein homeostasis and an immune regulator. In both capacities, HSP70 has been implicated in muscle disorders, yet with fragmented and differing results. In this study we aimed to compare results obtained in the mouse model for the severest form of muscular dystrophy (MD) equivalent to Duchenne MD, termed the mdx mouse, with results obtained in human MD.METHODS: Skeletal muscle and serum samples were obtained from 11 healthy controls, 11 fully characterized patients diagnosed with Becker MD and limb girdle MD (LGMD), and six muscle disease controls. In addition, muscle extracts were prepared from tibialis anterior of mdx and control mice at ages 4, 8 and 12 weeks. The HSP70 levels were quantified using RT-PCR, western blotting and protein arrays, and localized in muscle tissue sections using double immunofluorescence.RESULTS: We found selective and significant 2.2-fold upregulation of HSP70 protein in mdx tibialis muscle at the earliest disease phase only. In LGMD and Becker MD patients, HSP70 protein levels were not significantly different from those of healthy muscle and serum. HSP70 was localized to regenerating muscle fibers both in mouse and human MD skeletal muscle tissues. Toll-like receptor (TLR) 2 and TLR4 expression was moderately increased on the sarcolemma in MD muscle, yet protein levels were not significantly different from normal controls.CONCLUSIONS: HSP70 upregulation in MD appears disease stage-dependent, marking the phase of most active muscle regeneration in the mdx mouse. We postulate that well-timed supportive therapeutic interventions with HSP70 agonists could potentially improve muscle tissue's regenerative capacities in MD, attenuating loss of muscle mass while we await gene therapies to become more widely available.