Abstract
A description of the intracellular mechanisms that modulate skeletal muscle atrophy in early vertebrates is still lacking. In this context, we used the fine flounder, a unique and intriguing fish model, which exhibits remarkably slow growth due to low production of muscle-derived IGF-I, a key growth factor that has been widely acknowledged to prevent and revert muscle atrophy. Key components of the atrophy system were examined in this species using a detailed time-course of sampling points, including two contrasting nutritional periods. Under basal conditions high amounts of the atrogenes MuRF-1 and Atrogin-1 were observed. During fasting, the activation of the P38/MAPK and Akt/FoxO signaling pathways decreased; whereas, the activation of the IκBα/NFκB pathway increased. These changes in signal transduction activation were concomitant with a strong increase in MuRF-1, Atrogin-1, and protein ubiquitination. During short-term refeeding, the P38/MAPK and Akt/FoxO signaling pathways were strongly activated, whereas the activation of the IκBα/NFκB pathway decreased significantly. The expression of both atrogenes, as well as the ubiquitination of proteins, dropped significantly during the first hour of refeeding, indicating a strong anti-atrophic condition during the onset of refeeding. During long-term refeeding, Akt remained activated at higher than basal levels until the end of refeeding, and Atrogin-1 expression remained significantly lower during this period. This study shows that the components of the atrophy system in skeletal muscle appeared early in the evolution of vertebrates and some mechanisms have been conserved, whereas others have not. These results represent an important achievement for the area of fish muscle physiology, showing an integrative view of the atrophy system in a non-mammalian species and contributing to novel insights on the molecular basis of muscle growth regulation in earlier vertebrates.
Highlights
The maintenance of skeletal muscle mass is a complex and controlled process that is largely influenced by the nutritional and physiological state of the animal
Signaling Pathways Involved in Muscle Atrophy Linked to Atrogenes Expression and Protein Ubiquitination in Muscle of the Fine Flounder By evaluating the transcriptional regulation of MuRF-1 and Atrogin-1, a quite dissimilar pattern is observed via different temporal changes and abundances of these atrogenes
MuRF1 mRNA is more abundant than Atrogin-1 mRNA, with equivalent expression levels of structural muscle proteins and house-keeping genes (MuRF-1 (Ct = 21), b-tubulin (Ct = 25), b-actin (Ct = 21), Fau (Ct = 23)) [Fuentes EN, Safian D, Valdes JA, Molina A. 2012. unpublished data]
Summary
The maintenance of skeletal muscle mass is a complex and controlled process that is largely influenced by the nutritional and physiological state of the animal. Polyubiquitination of proteins is a multiple-step process that requires ATP and the participation of three components in the formation of the ubiquitin-protein complexes, the ubiquitinactivating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-ligase (E3) [6,7,8], in order to covalently attach multiple ubiquitin molecules to the protein substrate [6] These tagged proteins are recognized and degraded by the 26S proteasome, resulting in short peptides [8]. Numerous ubiquitin-ligases have been identified; differential expression screening studies, originally planned to detect high-fidelity markers of muscle atrophy, led to the discovery of two genes that encode ubiquitinligases, MuRF-1 (Muscle Ring Finger protein-1) and Atrogin-1 ( called Muscle Atrophy F-box (MAFbx) [10], which have been shown to be upregulated in several models of skeletal muscle atrophy, validating them as reliable markers of atrophy [11,12,13]
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