Dietary Restriction, mt DNA Abnormalities and Aging

描述：（逐字从应用程序）老化被认为是一个复杂的 全球性的生理损耗许多生理上重要的 年龄相关的变化表现在非复制性组织如脑， 心脏和骨骼肌严重依赖于氧化代谢来获取能量。 在骨骼肌中，我们假设线粒体遗传和酶 可能继发于终生氧化损伤的异常， 破坏细胞过程或引发细胞死亡。随之而来的骨骼肌 纤维功能障碍或损失可能会导致肌肉减少症，年龄相关的损失， 骨骼肌质量和功能。 我们通过对老年人骨骼肌的原位分析， 啮齿动物，线粒体异常的生物学影响问题。 我们的研究表明，一个特定的事件序列连接mtDNA缺失， 肌肉减少症伴随着肌肉质量和纤维数量的减少， 观察到节段性线粒体异常增加， 激光捕获显微切割显示的特异性rntDNA缺失突变 和全线粒体基因组扩增。携带线粒体DNA的肌纤维 缺失突变通常表现为萎缩、分裂和氧化损伤 证明了这些异常对细胞的影响。这些相关性 提示mtDNA缺失突变在肌少症中因果作用。 本提案的目标有四个方面：1）描述ETS的特征 异常，纤维萎缩，纤维分裂和氧化损伤， 在选定的大鼠肌肉中的肌肉减少症的进展; 2）确定细胞的 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纤维3）评估早期和 成人发作的热量限制对肌肉减少症进展的影响 F344 BNF 1的选定肌肉中线粒体异常的积累 大鼠; 4）确定是否线粒体基因组携带缺失突变 与年龄相关的ETS异常和随后的 细胞影响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.