Regulation of skeletal muscle atrophy by the ZEB1 transcription factor
[eng] Muscle atrophy, which is characterized by excessive protein catabolism, is one of the major adaptive processes that occur in several physiopathological and clinical conditions, to counteract stressing stimuli. Skeletal muscle atrophy is triggered by the induction of a group of proteins (atroge...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/173102 |
| Acceso en línea: | https://hdl.handle.net/2445/173102 http://hdl.handle.net/10803/670366 |
| Access Level: | acceso abierto |
| Palabra clave: | Múscul estriat Atròfia muscular Metabolisme Regulació genètica Striated muscle Muscular atrophy Metabolism Genetic regulation |
| Sumario: | [eng] Muscle atrophy, which is characterized by excessive protein catabolism, is one of the major adaptive processes that occur in several physiopathological and clinical conditions, to counteract stressing stimuli. Skeletal muscle atrophy is triggered by the induction of a group of proteins (atrogenes) that includes components of the ubiquitin–proteasome and autophagy-lysosomal systems. Atrogenes are induced by FOXO transcription factors, but their regulation had not been fully dissected. In this dissertation, it has been studied the role of the transcription factor ZEB1, best known for promoting tumor progression, in muscle atrophy induced by disuse and fasting. It was found that, in both conditions, ZEB1 inhibited muscle atrophy, but through different mechanisms. In disuse-induced atrophy, ZEB1 antagonized FOXO3- mediated induction of atrogenes, while during fasting ZEB1 promoted the expression of NRF1 and NRF2, two important mitochondrial and oxidative stress regulatory genes. During hindlimb immobilization, global Zeb1 heterozygous deletion results in enhanced muscle atrophy and higher expression of a number of atrogenes, including Atrogin-1/Fbxo32 and MuRF1/Trim63. Mechanistically, ZEB1 directly represses in vitro and in vivo Fbxo32 and Trim63 promoter transcription in a stage-dependent manner and in a reverse pattern with MYOD1. ZEB1 binds to the Fbxo32 promoter in undifferentiated myoblasts and atrophic myotubes, but not in non-atrophic myotubes, where it is displaced by MYOD1. ZEB1 represses both promoters through CtBP- mediated inhibition of FOXO3 transcriptional activity. Using a conditional muscle-specific Zeb1 knockout mouse model, it was found that ZEB1 promoted the formation of oxidative slow-type I fibers, through the induction of MEF2C and PGC1ß. During fasting-induced muscle atrophy, the specific knock out of Zeb1 in myofibers induced higher muscle atrophy (Zeb1 KO muscles have an increased number of fibers with lower CSA), lower mitochondrial respiration, due to mitochondrial complex III dysfunction, and higher ROS production. ZEB1 directly binds to Nrf1 and Nrf2 promoters, two key regulatory genes of mitochondrial biogenesis and oxidative stress. Altogether, these results set ZEB1 as a key driver of muscle atrophy, highlighting its importance as a possible new target in therapeutic approaches to clinical conditions causing muscle mass loss. |
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