Lo Harriet P, Nixon Susan J, Hall Thomas E, Cowling Belinda S, Ferguson Charles, Morgan Garry P, Schieber Nicole L, Fernandez-Rojo Manuel A, Bastiani Michele, Floetenmeyer Matthias, Martel Nick, Laporte Jocelyn, Pilch Paul F, Parton Robert G
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique UMR7104, Strasbourg University, Illkirch 67404, France.
J Cell Biol. 2015 Aug 31;210(5):833-49. doi: 10.1083/jcb.201501046.
Dysfunction of caveolae is involved in human muscle disease, although the underlying molecular mechanisms remain unclear. In this paper, we have functionally characterized mouse and zebrafish models of caveolae-associated muscle disease. Using electron tomography, we quantitatively defined the unique three-dimensional membrane architecture of the mature muscle surface. Caveolae occupied around 50% of the sarcolemmal area predominantly assembled into multilobed rosettes. These rosettes were preferentially disassembled in response to increased membrane tension. Caveola-deficient cavin-1(-/-) muscle fibers showed a striking loss of sarcolemmal organization, aberrant T-tubule structures, and increased sensitivity to membrane tension, which was rescued by muscle-specific Cavin-1 reexpression. In vivo imaging of live zebrafish embryos revealed that loss of muscle-specific Cavin-1 or expression of a dystrophy-associated Caveolin-3 mutant both led to sarcolemmal damage but only in response to vigorous muscle activity. Our findings define a conserved and critical role in mechanoprotection for the unique membrane architecture generated by the caveolin-cavin system.
小窝功能障碍与人类肌肉疾病有关，尽管其潜在的分子机制仍不清楚。在本文中，我们对与小窝相关的肌肉疾病的小鼠和斑马鱼模型进行了功能表征。利用电子断层扫描技术，我们定量确定了成熟肌肉表面独特的三维膜结构。小窝占据了肌膜面积的50%左右，主要组装成多叶玫瑰花结。这些玫瑰花结在膜张力增加时优先解体。缺乏小窝的小窝蛋白-1基因敲除（cavin-1(-/-)）肌肉纤维显示出肌膜组织的显著丧失、异常的T小管结构以及对膜张力的敏感性增加，而肌肉特异性小窝蛋白-1的重新表达可挽救这种情况。对活斑马鱼胚胎的体内成像显示，肌肉特异性小窝蛋白-1的缺失或与营养不良相关的小窝蛋白-3突变体的表达均会导致肌膜损伤，但仅在剧烈肌肉活动时出现。我们的研究结果确定了小窝蛋白-小窝蛋白系统产生的独特膜结构在机械保护中的保守关键作用。
