Dietary Restriction, mt DNA Abnormalities and Aging

描述：(逐字来自应用程序)衰老被认为是一种错综复杂的 全球性、生理性减员的网络。许多具有生理意义的 与年龄相关的变化表现在非复制组织，如脑， 严重依赖氧化代谢提供能量的心脏和骨骼肌。 在骨骼肌中，我们假设线粒体遗传和酶 异常，可能继发于终生氧化损伤，最终可能 扰乱细胞进程或引发细胞死亡。随之而来的骨骼肌 纤维功能障碍或丢失可能导致骨质疏松症，即与年龄相关的 骨骼肌质量和功能。 我们正在通过对老年人骨骼肌的原位分析来解决 啮齿动物，线粒体异常对生物影响的问题。 我们的研究表明，线粒体DNA缺失与 石棺减少症。伴随着肌肉质量和纤维数量的减少，我们有 观察到节段性线粒体异常增加，其中包含 激光捕获显微切割技术揭示rntDNA的特异性缺失突变 和线粒体全基因组扩增。含有线粒体DNA的肌肉纤维 缺失突变通常表现为萎缩、分裂和氧化损伤 显示了这些异常对细胞的影响。这些相关性 提示线粒体DNA缺失突变在骨质疏松症中起了因果作用。 本提案的目的有四个：1)确定ETS的特征 异常、纤维萎缩、纤维分裂和氧化损伤 选定的大鼠肌肉中肌肉量减少的进展；2)确定细胞 基因表达谱对年龄相关ETS异常片段的影响 激光捕获显微切割的肌肉纤维3)评估早期和 成人开始的热量限制对骨质疏松症进展的影响 F344BNF1部分肌肉线粒体异常的积累 4)确定线粒体基因组是否存在缺失突变 与年龄相关的ETS异常和随后的 细胞撞击。这项工作的结果将进一步阐明 这些突变的生物学意义以及它们对 与年龄相关的肌肉生理和结构变化。

DESCRIPTION: (Verbatim from application) Aging is recognized as an intricate web of global, physiological attrition. Many of the physiologically significant age-related changes are exhibited in non-replicative tissues such as brain, heart and skeletal muscle that rely heavily on oxidative metabolism for energy. In skeletal muscle, we hypothesize that mitochondrial genetic and enzymatic abnormalities, possibly secondary to life-long oxidative damage, may ultimately disrupt cellular processes or trigger cell death. The ensuing skeletal muscle fiber dysfunction or loss may contribute to sarcopenia, the age-related loss of skeletal muscle mass and function. We are addressing, by the in situ analyses of skeletal muscle from aged rodents, the question of the biological impact of mitochondrial abnormalities. Our studies suggest a specific sequence of events linking mtDNA deletions to sarcopenia. Concomitant with decreased muscle mass and fiber number, we have observed increases in segmental mitochondrial abnormalities that contain specific rntDNA deletion mutations as revealed by laser capture microdissection and whole mitochondrial genome amplification. Muscle fibers harboring mtDNA deletion mutations often display atrophy, splitting and oxidative damage demonstrating a cellular impact of these abnormalities. These correlations suggest a causal role for mtDNA deletion mutations in sarcopenia. The aims of the present proposal are four-fold: 1) characterize ETS abnormalities, fiber atrophy, fiber splitting and oxidative damage during the progression of sarcopenia in selected rat muscles; 2) ascertain the cellular impact of age-associated ETS abnormal segments by gene expression profiling of laser-capture microdissected muscle fibers 3) Assess the effect of early- and adult-onset caloric restriction on the progression of sarcopenia and the accumulation of mitochondrial abnormalities in selected muscles of F344BNF1 rats; 4) determine whether mitochondrial genomes harboring deletion mutations are causally related to age-associated ETS abnormalities and subsequent cellular impact. The outcome of this work will shed additional light on the biological significance of these mutations and the effects they have on the age-related changes in muscle physiology and structure.