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）：重要的骨骼肌萎缩会导致功能独立性和生活质量的丧失，以及诸如抵抗运动训练之类的干预措施在恢复老年人的肌肉质量方面尚未完全有效。与年龄相关的萎缩以及超负荷诱导肥大的能力降低，主要发生在衰老的骨骼肌的快速纤维中。静息骨骼肌蛋白的合成率和转化效率随着年龄的增长而下降，我们的数据表明，5'-AMP激活蛋白激酶的磷酸化（AMPK; AMPK;抑制蛋白质翻译和合成）在快速和过度载荷的骨骼骨骼骨骼骨骼骨骼骨骼的快速特异性方式中随着年龄的增长而上调。此外，AMPK磷酸化与快速交换肌肉中超载诱导的肥大的程度紧密相关。这项研究的第一个目的是确定升高AMPK活性是否导致与年龄相关的蛋白质合成率下降，而蛋白质合成率在静止的旧动物的快速束缚骨骼肌中。年轻成年人（Ya; 8 mo。），中年（Ma; 19 mo。）和旧的（O 30 mo。）男性Fisher 344 X棕色挪威大鼠将获得单一注射盐水或AMPK激活剂AICAR（5-氨基氨基咪唑-4-氨基二酰胺-4-carboxamide-carboxamide-1-beta-d-beta-dribofuranoside）。在快速两次的plantaris（PLT）肌肉中，AMPK磷酸化/活性，混合和肌原纤维蛋白合成的速率（通过3H-苯丙氨酸掺入），影响AMPK活性的AMPK-Y亚基，以及潜在的信号中的信号中间体，可控制AMPK的蛋白质转化。我们假设ALCAR刺激的AMPK-Q2活性将抑制年轻成人和中年动物的快速twitch plantaris肌肉中的混合和肌原纤维蛋白的合成速率，从旧盐水治疗的动物中看到的水平。这项研究的第二个目的是确定AMPK活性升高是否导致蛋白质合成率的下降以及与老动物的超载快速骨骼骨骼肌相关的年龄相关的肥大能力下降。 YA，MA和O雄性FBN大鼠将进行胃肌的单侧外科手术消融，以长期将快速交换PLT肌肉超负荷7天，在此期间，AICAR或盐水将长期进行。 7天后，AMPK磷酸化/活性，混合和肌原纤维蛋白合成的速率，肥大，AMPK-Y亚基和信号传导中间体将再次在PLT中再次测量。我们假设ALCAR刺激的AMPK-A2活性将抑制静脉混合和肌原纤维蛋白的合成速率和YA和MA动物的超载快速肌肉肌肉的肥大，并在O盐水处理的动物中看到的水平。这项调查的长期目标是阐明萎缩和衰老快速骨骼骨骼肌肉的肥大的基础机制，为本科和研究生提供研究机会，并提供数据以建立未来R01赠款应用的数据。