The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes
The TORC1/P70S6K and TORC1/4EBP1 signaling pathways have a stronger contribution on skeletal muscle growth than MAPK/ERK in an early vertebrate: Differential involvement of the IGF system and atrogenes
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DOI：
10.1016/j.ygcen.2014.10.012
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发表时间：
2015-01-01
影响因子：
2.7
通讯作者：
Molina, Alfredo
中科院分区：
文献类型：
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作者：
Fuentes, Eduardo N.;Eir Einarsdottir, Ingibjoerg;Molina, Alfredo
关于潜在机制的知识，特别是早期脊椎动物体内肌肉生长的信号通路的知识仍然很少。将鱼（Paralichthys adspersus）禁食 3 周，以诱导强烈肌肉萎缩的分解代谢期。随后，将鱼重新喂食两周以诱导代偿性肌肉肥大。在重新喂食期间，每天用雷帕霉素（TORC 阻断剂）、P098059（MEK 阻断剂）或 PBS（V；媒介物）处理鱼，或不进行处理（C；对照）。雷帕霉素和P098059对体内肌肉细胞结构、生长性能和生长相关基因的表达有不同程度的损害，并且TORC1的抑制比MAPK的抑制对鱼肌肉生长的影响更大。阻断TORC1会抑制TORC1激活的两个下游成分P70S6K和4EBP1的磷酸化，从而影响肌肉中的蛋白质含量。与此同时，肌肉中igf-1、2和igfbp-4、5的基因表达下调，而atrogin-1、murf-1和igfbp-2、3的表达上调。肌肉肥大被废除，促进肌肉萎缩，最终影响体重。 TORC2 复合物不受雷帕霉素的影响。另一方面，PD98059 治疗触发了 ERK 失活，ERK 是 MEK 激活的下游成分。肌肉中igf-1 mRNA含量下调，肌肉肥大部分受损。本研究首次提供了早期脊椎动物骨骼肌中TORC1/P70S6K、TORC1/4EBP1和MAPK/ERK信号通路的体内贡献的直接数据，并强调了TORC1在从细胞到有机体水平的生长中的超验作用。 (C) 2014 Elsevier Inc. 保留所有权利。
Knowledge about the underlying mechanisms, particularly the signaling pathways that account for muscle growth in vivo in early vertebrates is still scarce. Fish (Paralichthys adspersus) were fasted for 3 weeks to induce a catabolic period of strong muscle atrophy. Subsequently, fish were refed for 2 weeks to induce compensatory muscle hypertrophy. During refeeding, the fish were treated daily with either rapamycin (TORC blocker), P098059 (MEK blocker), or PBS (V; vehicle), or were untreated (C; control). Rapamycin and P098059 differentially impaired muscle cellularity in vivo, growth performance, and the expression of growth-related genes, and the inhibition of TORC1 had a greater impact on fish muscle growth than the inhibition of MAPK. Blocking TORC1 inhibited the phosphorylation of P70S6K and 4EBP1, two downstream components activated by TORC1, thus affecting protein contents in muscle. Concomitantly, the gene expression in muscle of igf-1, 2 and igfbp-4, 5 was down-regulated while the expression of atrogin-1, murf-1, and igfbp-2, 3 was up-regulated. Muscle hypertrophy was abolished and muscle atrophy was promoted, which finally affected body weight. TORC2 complex was not affected by rapamycin. On the other hand, the PD98059 treatment triggered ERK inactivation, a downstream component activated by MEK. mRNA contents of igf-1 in muscle were down-regulated, and muscle hypertrophy was partially impaired. The present study provides the first direct data on the in vivo contribution of TORC1/P70S6K, TORC1/4EBP1, and MAPK/ERK signaling pathways in the skeletal muscle of an earlier vertebrate, and highlights the transcendental role of TORC1 in growth from the cellular to organism level. (C) 2014 Elsevier Inc. All rights reserved.