血管紧张素II型1受体敲除对大鼠比目鱼肌废用性肌萎缩的性别特异性保护作用。

IF 3.3 3区 医学 Q1 PHYSIOLOGY
Toshinori Yoshihara, Mizuki Takaragawa, Shohei Dobashi, Hisashi Naito
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引用次数: 0

摘要

骨骼肌不使用导致萎缩。越来越多的证据表明血管紧张素II型1受体(AT1R)参与性别依赖性分解代谢信号传导。然而,AT1R在骨骼肌中的直接作用尚不清楚。本研究探讨了通过腺相关病毒血清型9 (AAV9)介导的短发夹RNA (shRNA)递送选择性抑制AT1R在大鼠比目肌中的表达是否可以减轻后肢卸载(HU)诱导的肌肉萎缩,以及这种作用在雄性和雌性大鼠之间是否存在差异。雄性和雌性大鼠分别在比目鱼肌肌内注射编码at1r靶向shRNA的AAV9载体。HU 7 d后,评估AT1R基因拷贝数(数字PCR)、受体丰度(配体结合试验)、肌纤维横截面积(CSA)和下游分子标记(包括磷酸化Smad2/3和Smad1/5/8、HDAC4表达、atrogenes、Fbxo32和Trim63)。雌性大鼠表现出更高的AT1R基因拷贝数,AAV9-shRNA选择性地减少了AT1R基因拷贝数。配体结合证实了两性中受体丰度的降低。CSA损耗衰减仅在女性中观察到,特别是在I型纤维中。在雌性动物中,AT1R敲低显著增加Smad1/5/8磷酸化,降低HDAC4表达。AT1R拷贝数与Fbxo32和Trim63表达呈正相关,与AAV剂量无关。AT1R在废用诱导的肌肉萎缩中发挥性别特异性作用,因为肌肉特异性AT1R敲低在雌性大鼠中具有选择性保护作用。这种作用似乎是通过Smad1/5/8-HDAC4信号传导介导的,而不是氧化应激或自噬。这项研究为针对肌肉定位肾素-血管紧张素系统的治疗策略提供了机制支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sex-specific protective effects of angiotensin II type 1 receptor knockdown on disuse muscle atrophy in the rat soleus muscle.

Skeletal muscle disuse leads to atrophy. Accumulating evidence suggests that angiotensin II type 1 receptor (AT1R) contributes to sex-dependent catabolic signaling. However, the direct role of AT1R in skeletal muscle is unclear. This study investigated whether selective suppression of AT1R expression in the rat soleus muscle via adeno-associated virus serotype 9 (AAV9)-mediated short hairpin RNA (shRNA) delivery could mitigate hindlimb unloading (HU)-induced muscle atrophy, and whether this effect differed between male and female rats. Male and female rats received intramuscular injections of AAV9 vectors encoding AT1R-targeted shRNA into the soleus muscle. After 7 d of HU, AT1R gene copy number (digital PCR), receptor abundance (ligand binding assay), muscle fiber cross-sectional area (CSA), and downstream molecular markers (including phosphorylated Smad2/3 and Smad1/5/8, HDAC4 expression, and the atrogenes, Fbxo32 and Trim63) were assessed. Female rats exhibited substantially higher AT1R gene copy numbers, which were selectively reduced by AAV9-shRNA. Ligand binding confirmed reduced receptor abundance in both sexes. CSA loss attenuation was observed exclusively in females, particularly in type I fibers. In female animals, AT1R knockdown substantially increased Smad1/5/8 phosphorylation and decreased HDAC4 expression. The AT1R copy number was positively correlated with Fbxo32 and Trim63 expression, independent of AAV dose. AT1R plays a sex-specific role in disuse-induced muscle atrophy, as muscle-specific AT1R knockdown conferred selective protection in female rats. The effect appears to be mediated via Smad1/5/8-HDAC4 signaling rather than oxidative stress or autophagy. This study provides mechanistic support for sex-informed therapeutic strategies targeting the muscle-localized renin-angiotensin system.

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来源期刊
CiteScore
6.00
自引率
9.10%
发文量
296
审稿时长
2-4 weeks
期刊介绍: The Journal of Applied Physiology publishes the highest quality original research and reviews that examine novel adaptive and integrative physiological mechanisms in humans and animals that advance the field. The journal encourages the submission of manuscripts that examine the acute and adaptive responses of various organs, tissues, cells and/or molecular pathways to environmental, physiological and/or pathophysiological stressors. As an applied physiology journal, topics of interest are not limited to a particular organ system. The journal, therefore, considers a wide array of integrative and translational research topics examining the mechanisms involved in disease processes and mitigation strategies, as well as the promotion of health and well-being throughout the lifespan. Priority is given to manuscripts that provide mechanistic insight deemed to exert an impact on the field.
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