Dietary Restriction, mt DNA Abnormalities and Aging

饮食限制、mt DNA 异常和衰老

• 批准号: 6620054
• 负责人: JUDD M. AIKEN
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-10 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620054
• 关键词: aging; apoptosis; atrophy; bioenergetics; caloric dietary content; dietary restriction; electron transport; gene deletion mutation; gene expression; gene expression profiling; genome; histochemistry /cytochemistry; laboratory rat; laser capture microdissection; microarray technology; mitochondrial DNA; mitochondrial disease /disorder; muscle cells; nutrition of aging; nutrition related tag; oxidative stress; pathologic process; polymerase chain reaction; sarcopenia

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.

描述：（逐字化的应用程序）衰老被认为是复杂的 全球生理损耗的网络。许多生理意义 与年龄相关的变化在非复制组织（例如大脑）中表现出来 严重依赖氧化代谢的心脏和骨骼肌。 在骨骼肌中，我们假设线粒体遗传和酶促 异常，可能是终身氧化损害的继发的，最终可能 破坏细胞过程或触发细胞死亡。随后的骨骼肌 纤维功能障碍或损失可能导致肌肉减少症，与年龄有关的损失 骨骼肌质量和功能。 我们正在通过对年龄的骨骼肌进行原位分析来解决 啮齿动物，线粒体异常的生物学影响问题。 我们的研究表明，将mtDNA缺失与 肌肉减少症。与肌肉质量和纤维数量减少同时，我们有 观察到的分段线粒体异常的增加 通过激光捕获微分解显示的特定rntDNA缺失突变 和整个线粒体基因组扩增。带有mtDNA的肌肉纤维 缺失突变通常显示出萎缩，分裂和氧化损伤 证明了这些异常的细胞影响。这些相关性 提出了肌肉减少症mtDNA缺失突变的因果作用。 本提案的目的是四倍：1）表征ET 在此期间，异常，纤维萎缩，纤维分裂和氧化损伤 选定大鼠肌肉中肌肉减少症的进展； 2）确定细胞 通过基因表达分析的年龄相关ETS异常段的影响 激光捕获显微解剖的肌肉纤维3）评估早期和早期和 成人发作的热量限制肌肉减少症和 F344BNF1选定肌肉中线粒体异常的积累 老鼠； 4）确定线粒体基因组是否具有缺失突变 与年龄相关的ETS异常和随后的因果关系有关 细胞影响。这项工作的结果将为 这些突变的生物学意义及其对 与年龄相关的肌肉生理和结构的变化。