Gain-of-function R225Q Mutation in AMP-activated Protein Kinase γ3 Subunit Increases Mitochondrial Biogenesis in Glycolytic Skeletal Muscle
Gain-of-function R225Q Mutation in AMP-activated Protein Kinase γ3 Subunit Increases Mitochondrial Biogenesis in Glycolytic Skeletal Muscle
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DOI：
10.1074/jbc.m805078200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Zierath, Juleen R.
中科院分区：
文献类型：
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作者：
Garcia-Roves, Pablo M.;Osler, Megan E.;Zierath, Juleen R.
AMP活化蛋白激酶（AMPK）是由催化亚基（α）和两个调节亚基（β和γ）组成的异源三聚体复合物，其作为细胞能量传感器工作。多种异三聚体复合物的存在为这种高度保守的信号系统的多种作用提供了分子基础。AMPK γ 3亚基主要在骨骼肌中表达，主要在II型糖酵解纤维类型中。我们确定AMPK γ 3亚基是否在介导骨骼肌线粒体生物合成的信号通路中起作用。我们提供的证据表明，AMPK γ 3亚基的过度表达或消融似乎并没有发挥关键作用，在定义线粒体含量在静息骨骼肌。然而，AMPK γ 3亚基（Tg-AMPK γ 3（225 Q））的突变形式（R225 Q）的过表达增加了糖酵解骨骼肌中的线粒体生物合成。这些适应与共激活因子PGC-1 α和几种调节线粒体生物发生的转录因子（包括NRF-1、NRF-2和TFAM）的表达增加有关。琥珀酸脱氢酶染色（单个纤维氧化特征的标志物）在Tg-AMPK γ 3（225 Q）小鼠白色腓肠肌的横向骨骼肌切片中也增加，与纤维类型组成的变化无关。总之，AMPK γ 3亚基中的单核苷酸突变（R225 Q）与糖酵解骨骼肌中的线粒体生物合成相关，伴随着共激活因子PGC-1 α和几种调节线粒体蛋白的转录因子的表达增加，而不改变纤维类型组成。
AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma), that works as a cellular energy sensor. The existence of multiple heterotrimeric complexes provides a molecular basis for the multiple roles of this highly conserved signaling system. The AMPK gamma 3 subunit is predominantly expressed in skeletal muscle, mostly in type II glycolytic fiber types. We determined whether the AMPK gamma 3 subunit has a role in signaling pathways that mediate mitochondrial biogenesis in skeletal muscle. We provide evidence that overexpression or ablation of the AMPK gamma 3 subunit does not appear to play a critical role in defining mitochondrial content in resting skeletal muscle. However, overexpression of a mutant form (R225Q) of the AMPK gamma 3 subunit (Tg-AMPK gamma 3(225Q)) increases mitochondrial biogenesis in glycolytic skeletal muscle. These adaptations are associated with an increase in expression of the co-activator PGC-1 alpha and several transcription factors that regulate mitochondrial biogenesis, including NRF-1, NRF-2, and TFAM. Succinate dehydrogenase staining, a marker of the oxidative profile of individual fibers, was also increased in transversal skeletal muscle sections of white gastrocnemius muscle from Tg-AMPK gamma 3(225Q) mice, independent of changes in fiber type composition. In conclusion, a single nucleotide mutation (R225Q) in the AMPK gamma 3 subunit is associated with mitochondrial biogenesis in glycolytic skeletal muscle, concomitant with increased expression of the co-activator PGC-1 alpha and several transcription factors that regulate mitochondrial proteins, without altering fiber type composition.