Aging, AMP Kinase and Skeletal Muscle Overload

衰老、AMP 激酶和骨骼肌超负荷

基本信息

批准号：
6954439
负责人：
SCOTT E GORDON
金额：
$ 19.24万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6954439
关键词：
adenosine kinase aging atrophy human old age (65+)laboratory rat muscle hypertrophy protein biosynthesis striated muscles

项目摘要

DESCRIPTION (provided by applicant): Significant skeletal muscle atrophy results in a loss of functional independence and quality of life, and interventions such as resistance exercise training are not fully effective in restoring muscle mass in elderly individuals. Age-related atrophy, as well as the diminished capacity for overload-induced hypertrophy, occur predominantly in fast-twitch fibers in aging skeletal muscle. Resting skeletal muscle protein synthesis rate and translational efficiency decline with age, and we have strong data showing that the phosphorylation of 5'-AMP- activated protein kinase (AMPK; which suppresses protein translation and synthesis) is upregulated with age in a fast-twitch-specific manner in resting and overloaded rat skeletal muscle. Moreover, AMPK phosphorylation was tightly and negatively correlated with the degree of overload-induced hypertrophy in fast-twitch muscles. The first aim of this investigation is to determine if elevated AMPK activity is responsible for the age-related decline in protein synthesis rate in resting fast-twitch skeletal muscles of old animals. Young adult (YA; 8 mo.), middle- aged (MA; 19 mo.), and old (O; 30 mo.) male Fisher 344 x Brown Norway rats will be given a single injection of saline or the AMPK activator AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside). In fast-twitch plantaris (PLT) muscles, AMPK phosphorylation/activity, rates of mixed and myofibrillar protein synthesis (via 3H- phenylalanine incorporation), AMPK-y subunits influencing AMPK activity, and potential signaling intermediates controlling protein translation downstream of AMPK will be measured. We hypothesize that AlCAR-stimulated AMPK-Q2 activity will suppress resting mixed and myofibrillar protein synthesis rates in fast-twitch plantaris muscles of young adult and middle-aged animals to the levels seen in old saline-treated animals. The second aim of this investigation is to determine if elevated AMPK activity is responsible for an age-related decline in protein synthesis rate and the age-related decline in hypertrophic capacity in overloaded fast-twitch skeletal muscles of old animals. YA, MA, and O male FBN rats will undergo unilateral surgical ablation of the gastrocnemius to chronically overload the fast-twitch PLT muscle for 7 days, during which AICAR or saline will be chronically administered. After 7 days, AMPK phosphorylation/activity, rates of mixed and myofibrillar protein synthesis, hypertrophy, AMPK-y subunits, and signaling intermediates will again be measured in the PLT. We hypothesize that AlCAR-stimulated AMPK-a2 activity will suppress resting mixed and myofibrillar protein synthesis rates and hypertrophy in overloaded fast-twitch PLT muscles of YA and MA animals to levels seen in O saline-treated animals. The long-term objectives of this investigation are to elucidate mechanisms underlying the atrophy and impaired hypertrophy of aging fast-twitch skeletal muscle, to provide research opportunities for undergraduate and graduate students, and to provide data on which to establish future R01 grant applications.

描述（由申请人提供）：显着的骨骼肌萎缩会导致功能独立性和生活质量的丧失，并且抗阻运动训练等干预措施对于恢复老年人的肌肉质量并不完全有效。与年龄相关的萎缩以及过载引起的肥大能力的减弱主要发生在衰老骨骼肌的快肌纤维中。静息骨骼肌蛋白质合成率和翻译效率随着年龄的增长而下降，我们有强有力的数据表明，5'-AMP 激活的蛋白激酶（AMPK；抑制蛋白质翻译和合成）的磷酸化随着年龄的增长而上调。 - 休息和超载的大鼠骨骼肌的特定方式。此外，AMPK 磷酸化与超负荷引起的快肌肥大程度呈紧密负相关。这项研究的首要目的是确定 AMPK 活性升高是否是老年动物静息快肌骨骼肌中蛋白质合成率与年龄相关的下降的原因。年轻成年（YA；8 个月）、中年（MA；19 个月）和老年（O；30 个月）雄性 Fisher 344 x Brown 挪威大鼠将接受单次注射生理盐水或 AMPK 激活剂 AICAR （5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核苷）。在快肌跖肌 (PLT) 肌肉中，AMPK 磷酸化/活性、混合蛋白和肌原纤维蛋白合成速率（通过 3H-苯丙氨酸掺入）、影响 AMPK 活性的 AMPK-y 亚基以及控制 AMPK 下游蛋白翻译的潜在信号传导中间体将受到影响。测量。我们假设 AlCAR 刺激的 AMPK-Q2 活性将抑制年轻成年和中年动物快肌跖肌中的静息混合蛋白和肌原纤维蛋白合成率，使其达到老年盐水处理动物的水平。这项研究的第二个目的是确定 AMPK 活性升高是否是导致老年动物超负荷快肌骨骼肌中与年龄相关的蛋白质合成率下降和与年龄相关的肥大能力下降的原因。 YA、MA 和 O 雄性 FBN 大鼠将接受腓肠肌的单侧手术消融，以使快肌 PLT 肌肉长期超负荷 7 天，在此期间将长期施用 AICAR 或盐水。 7 天后，将在 PLT 中再次测量 AMPK 磷酸化/活性、混合和肌原纤维蛋白合成速率、肥大、AMPK-y 亚基和信号中间体。我们假设 AlCAR 刺激的 AMPK-a2 活性将抑制 YA 和 MA 动物超载的快肌 PLT 肌肉的静息混合蛋白和肌原纤维蛋白合成率和肥大，达到 O 盐水处理动物的水平。这项研究的长期目标是阐明衰老快肌骨骼肌萎缩和肥大受损的机制，为本科生和研究生提供研究机会，并为未来 R01 拨款申请提供数据。