DIETARY RESTRICTION, MT DNA ABNORMALITIES AND AGING

在这次更新中，我们建议扩展我们对mtDNA的研究， 衰老过程中的异常 我们的努力集中在啮齿动物上 骨骼肌，表明与年龄相关的mtDNA缺失 在肌肉纤维的子集中积累到高水平， 与纤维的ETS异常区域相关。这些ETS异常 区域通常缺乏复合物IV活性（细胞色素c氧化酶;一些区域缺乏复合物IV活性）。 其亚基是mtDNA编码的），同时对 复合物II（琥珀酸脱氢酶;其完全由核编码）。 ETS异常纤维沿着长度的表征 确定了横截面积急剧减少的区域 这表明缺失的mtDNA、ETS异常和 纤维萎缩 我们的目标是进一步描述年龄相关的ETS异常 区域和相关的骨骼肌纤维萎缩。 自从ETS 异常区域是分段的，这些实验需要 肌纤维沿着其长度的表征。 五块肌肉， 其中三个表现出与年龄相关的萎缩，其特征在于， 不同年龄（成年至高龄）的F344 x BNF 1大鼠。 这些 研究将涉及肌肉减少症的测量（肌肉质量、纤维数量 和纤维面积）结合ETS活性的组织学分析， 存在缺失的mtDNA。 此外，我们还将讨论 ETS异常纤维通过分析纤维面积以及 纤维死亡的细胞指标（凋亡和坏死）。

In this renewal, we are proposing to extend our studies of mtDNA abnormalities in aging processes. Our efforts have focused on rodent skeletal muscle, demonstrating that age-associated mtDNA deletions accumulate to high levels in a subset of muscle fibers and are associated with ETS abnormal regions of the fibers. These ETS abnormal regions typically lacked complex IV activity (cytochrome c oxidase; some subunits of which are mtDNA-encoded) while being hyperreactive for complex II (succinate dehydrogenase; which is entirely nuclear-encoded). The characterization of ETS abnormal fibers along their length identified regions which dramatically decreased in cross sectional area suggesting an association between deleted mtDNAs, ETS abnormalities, and fiber atrophy. Our objective is to further characterize age-associated ETS abnormal regions and the associated atrophy of skeletal muscle fibers. Since ETS abnormal regions are segmental, these experiments require the characterization of muscle fibers along their length. Five muscles, three of which exhibit age-associated atrophy, will be characterized in F344 x BNF1 rats of various ages (adult to advanced old age). These studies will involve measures of sarcopenia (muscle mass, fiber number and fiber area) combined with histologic analyses of ETS activity and presence of deleted mtDNAs. We will, in addition, address the fate of ETS abnormal fibers through the analysis of fiber area as well as cellular indicators of fiber death (apoptosis and necrosis).