Dysferlin deficiency alters lipid metabolism and remodels the skeletal muscle lipidome in mice[S]
Dysferlin deficiency alters lipid metabolism and remodels the skeletal muscle lipidome in mice[S]
复制标题
Dysferlin缺乏改变小鼠脂质代谢并重塑骨骼肌脂质组[S]
DOI：
10.1194/jlr.m090845
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发表时间：
2019-08-01
影响因子：
6.5
通讯作者：
Watt, Matthew J.
中科院分区：
文献类型：
--
作者：
Haynes, Vanessa R.;Keenan, Stacey N.;Watt, Matthew J.
编码 Dysferlin（一种膜相关蛋白）的基因缺陷会影响许多组织，包括骨骼肌，从而导致称为 Dysferlin 病的肌病。肥胖症表现为生长后骨骼肌功能逐渐丧失、早期肌细胞内脂质积累以及随后选择性肌肉被脂肪细胞明显替代。为了更好地了解导致这种疾病的变化，我们使用年轻成年 Dysferlin 缺陷雄性 BLAJ 小鼠和年龄匹配的 C57Bl/6J WT 小鼠评估了全身能量稳态、骨骼肌脂肪酸代谢、脂肪组织中的脂肪分解和骨骼肌脂质组。 BLAJ 小鼠的瘦体重增加，脂肪量减少，这与体力活动增加和脂肪组织脂解作用增加有关。 BLAJ 小鼠的骨骼肌脂肪酸代谢被重塑，其特征是脂肪酸分配为储存而不是氧化。脂质组学分析发现，BLAJ 小鼠骨骼肌中几乎所有脂质类别都发生了显着变化，包括鞘脂、磷脂、胆固醇和大多数甘油脂，但令人惊讶的是，三酰基甘油没有。这些观察结果表明，dysferlin 缺乏的早期表现是骨骼肌和脂肪组织脂质代谢的重新编程，这可能导致 Dysferlin 病中进行性不良组织病理学。
Defects in the gene coding for dysferlin, a membrane-associated protein, affect many tissues, including skeletal muscles, with a resultant myopathy called dysferlinopathy. Dysferlinopathy manifests postgrowth with a progressive loss of skeletal muscle function, early intramyocellular lipid accumulation, and a striking later replacement of selective muscles by adipocytes. To better understand the changes underpinning this disease, we assessed whole-body energy homeostasis, skeletal muscle fatty acid metabolism, lipolysis in adipose tissue, and the skeletal muscle lipidome using young adult dysferlin-deficient male BLAJ mice and age-matched C57Bl/6J WT mice. BLAJ mice had increased lean mass and reduced fat mass associated with increased physical activity and increased adipose tissue lipolysis. Skeletal muscle fatty acid metabolism was remodeled in BLAJ mice, characterized by a partitioning of fatty acids toward storage rather than oxidation. Lipidomic analysis identified marked changes in almost all lipid classes examined in the skeletal muscle of BLAJ mice, including sphingolipids, phospholipids, cholesterol, and most glycerolipids but, surprisingly, not triacylglycerol. These observations indicate that an early manifestation of dysferlin deficiency is the reprogramming of skeletal muscle and adipose tissue lipid metabolism, which is likely to contribute to the progressive adverse histopathology in dysferlinopathies.