CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.
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DOI：
10.1172/jci162479
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发表时间：
2023-07-03
影响因子：
15.9
通讯作者：
Rane, Sushil G.
中科院分区：
文献类型：
--
作者：
Bahn, Young Jae;Yadav, Hariom;Piaggi, Paolo;Abel, Brent S.;Gavrilova, Oksana;Springer, Danielle A.;Papazoglou, Ioannis;Zerfas, Patricia M.;Skarulis, Monica C.;McPherron, Alexandra C.;Rane, Sushil G.
了解骨骼肌纤维比例是如何调节的对于了解肌肉功能至关重要。氧化和糖酵解骨骼肌纤维在收缩能力、线粒体活性和代谢特性方面不同。纤维型比例在正常生理和疾病状态下各不相同，尽管其潜在机制尚不清楚。在人类骨骼肌中，我们观察到氧化纤维和线粒体标记物与PPARGC 1A和CDK 4的表达水平呈正相关，与CDKN 2A的表达水平呈负相关，CDKN 2A是与2型糖尿病显著相关的基因座。表达组成型活性Cdk4的小鼠不能结合其抑制剂p16INK4a（CDKN2A基因座的产物），从而免受肥胖和糖尿病的影响。他们的肌肉表现出增加的氧化纤维，改善线粒体特性，并增强葡萄糖摄取。相反，Cdk4的丢失或骨骼肌特异性缺失Cdk4的靶点E2F3，消耗氧化肌纤维，恶化线粒体功能，降低运动能力，同时增加糖尿病易感性。E2F3以Cdk4依赖的方式激活线粒体传感器PPARGC 1A。CDK4、E2F3和PPARGC1A水平与运动和健身呈正相关，与肥胖、胰岛素抵抗和人类和啮齿动物肌肉中的脂质积累呈负相关。总之，这些研究结果提供了机制的骨骼肌纤维规格的调节，是相关的代谢和肌肉疾病的见解。
Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle–specific deletion of Cdk4’s target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber–specification that is of relevance to metabolic and muscular diseases.
影响因子：
3.7
作者：
Lee JH;Jo J;Hardikar AA;Periwal V;Rane SG
通讯作者：
Rane SG