Molecular Mechanisms that Cause Muscle Atrophy

导致肌肉萎缩的分子机制

• 批准号: 7878091
• 负责人: ALFRED L GOLDBERG
• 金额: $ 39.15万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878091
• 关键词: Accounting; Aging; Applications Grants; Atrophic; Autophagocytosis; Binding; Binding Proteins; Biochemical; Biomedical Research; Cachexia; Cells; Denervation; Disease; Exercise; Family member; Fasting; Fiber; Genes; Genetic Transcription; Genome; Glucocorticoids; Goals; Grant; Homologous Gene; Human; In Vitro; Kidney Failure; Learning; Lysosomes; Malignant Neoplasms; Methods; Microarray Analysis; Mitochondria; Modeling; Molecular; Muscle; Muscle Proteins; Muscular Atrophy; Pathway interactions; Process; Proteins; Proteolysis; Regulation of Proteolysis; Relative (related person); Research; Research Institute; Resistance; Role; Sepsis; Skeletal Muscle; Systemic disease; Testing; Transcription Coactivator; Translational Research; Ubiquitin; United States National Institutes of Health; base; cofactor; drug development; falls; improved; in vivo; inhibitor/antagonist; interest; multicatalytic endopeptidase complex; muscle RING finger 1; muscle form; nerve injury; novel; overexpression; prevent; protein degradation; protein expression; public health relevance; response; transcription factor; ubiquitin ligase; ubiquitin-protein ligase; wasting

DESCRIPTION (provided by applicant): Atrophy of skeletal muscle is a debilitating response to denervation, disuse, fasting, glucocorticoids, many systemic diseases (e.g. cancer cachexia, renal failure) and aging. We showed that these various types of rapid atrophy result primarily from accelerated protein breakdown, triggered by the activation of the FoxO transcription factors and alterations in the expression of a set of about 80 atrophy-related genes ("atrogenes"), including two muscle-specific ubiquitin ligases, MuRF1 and atrogin-1/MAFbx, whose dramatic induction is essential for rapid wasting. To understand the atrophy process, it will be important to learn more about MuRF1's function and cofactors in vivo and to identify the muscle proteins that MuRF1 targets for degradation during atrophy. We have identified new protein partners of MuRF1 (S5a and novel E2s) that enhance MuRF1- dependent proteolysis in vitro and protein substrates (including critical myofibrillar components) that are lost selectively during denervation atrophy. Their precise roles in the atrophy process will be elucidated. Although the accelerated proteolysis during atrophy is due primarily to activation of the ubiquitin-proteasome pathway, we recently found that FoxO3, denervation, and fasting also stimulate lysosomal proteolysis and autophagy by enhancing transcription of many autophagy-related (atg) genes. We hope to clarify how autophagy is activated and the relative importance of the autophagic and proteasomal pathways in the destruction of different muscle components, especially in the loss of mitochondria and myofibrillar proteins, during atrophy in vivo. To obtain a fuller understanding of the transcriptional changes during atrophy, we plan to use improved gene microarray technology to identify the complete set of atrogenes upregulated and down regulated similarly in various types of atrophy. These studies should also enable us to define the specific roles in activating these transcriptional changes of the three FoxO family members (FoxO1, 3, and 4) and of NFkB, which is also critical for atrophy. We hope to learn how these transcription factors influence atrogene expression, proteolysis, and cell mass and their importance in vivo in the atrophy induced by glucocorticoids, fasting, and denervation. We recently found that expression of the exercise-induced transcriptional coactivator, PGC-11, and its homolog, PGC-12 fall dramatically during various types of atrophy, but that maintaining PGC-11 expression at high levels inhibits the induction of atrogin-1 and MuRF1 and blocks atrophy. A major goal will be to elucidate the mechanisms by which PGC-11 normally inhibits atrogene expression and protein loss and is repressed during atrophy, and to learn whether PGC12 serves similar functions in preserving muscle mass. PUBLIC HEALTH RELEVANCE: The overall goal of the various studies described in this grant application is to clarify the biochemical and transcriptional mechanisms responsible for the accelerated protein degradation that causes the rapid atrophy of skeletal muscles with disuse or nerve injury and in various systemic diseases (e.g. cancer, sepsis, renal failure) and aging.

描述（由申请人提供）：骨骼肌的萎缩是对神经，废弃，禁食，糖皮质激素，许多全身性疾病（例如癌症恶病质，肾衰竭）和衰老的一种使人衰弱的反应。我们表明，这些各种类型的快速萎缩主要是由加速蛋白质分解而导致的，这是由Foxo转录因子的激活以及一组约80个与萎缩相关的基因（“ Atrogenes”）表达的变化触发的，其中包括两个肌肉特异性的泛素rigase，murf1和Atrogbs-introgin-introgin-introgin-1/Mafbx，其IS IS IS IS IS IS IS IS IS IS IS IS IS IS IS IS dramAmFATICT IS DRAMAMFAINT IS DRAMAMFATICT IS DRAMAMFATICT IS DRAMAMFATICT IS DRAMAMFANTIS IS DRAMAMFANTICTUCTICT。要了解萎缩过程，重要的是要进一步了解MURF1的功能和体内辅助因子，并确定MURF1在萎缩过程中靶向降解的肌肉蛋白。我们已经确定了MURF1（S5a和Neph News E2S）的新蛋白质伴侣，这些蛋白质在体外增强了MURF1依赖性蛋白水解和蛋白质底物（包括关键的肌原纤维成分），这些蛋白质底物在去神经萎缩期间有选择地丢失。它们在萎缩过程中的确切作用将被阐明。尽管萎缩期间加速的蛋白水解主要是由于泛素 - 蛋白酶体途径的激活，但我们最近发现FOXO3，神经膜和禁食也通过增强许多自噬相关（ATG）基因的转录来刺激溶酶体蛋白水解和自噬。我们希望澄清自噬的激活方式，以及自噬和蛋白酶体途径在破坏不同肌肉成分中的相对重要性，尤其是在体内萎缩期间线粒体和肌原纤维蛋白的丧失。为了更深入地了解萎缩期间的转录变化，我们计划使用改进的基因微阵列技术来识别在各种萎缩类型的萎缩中上调和下调的完整阳极基因。这些研究还应使我们能够定义激活三个FOXO家族成员（FOXO1、3和4）和NFKB的这些转录变化的特定作用，这对于萎缩也至关重要。我们希望学习这些转录因子如何影响垂体表达，蛋白水解和细胞质量及其在体内的重要性，在糖皮质激素，禁食和神经上造成的萎缩中。我们最近发现，运动诱导的转录共激活因子PGC-11及其同源物PGC-12在各种类型的萎缩期间急剧下降，但是高水平的PGC-11表达抑制了Atrogin-1和Murf1和Murf1和Murf1和Blocks trophss的诱导。一个主要目标是阐明PGC-11通常会抑制垂直激素表达和蛋白质丧失的机制，并在萎缩过程中受到抑制，并了解PGC12是否在保留肌肉质量方面具有相似的功能。 公共卫生相关性：本赠款应用中描述的各种研究的总体目标是阐明负责加速蛋白质降解的生化和转录机制，从而导致骨骼肌的快速萎缩或神经损伤以及各种全身性疾病（例如，癌症，sepsis，肾脏失败）和衰减。