IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and muRF1

Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite...

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Published inAmerican journal of physiology: endocrinology and metabolism Vol. 50; no. 4; pp. E591 - E601
Main Authors SACHECK, Jennifer M, OHTSUKA, Akira, MCLARY, S. Christine, GOLDBERG, Alfred L
Format Journal Article
LanguageEnglish
Published Bethesda, MD American Physiological Society 01.10.2004
Subjects
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Insulin
Muscular system
Proteins
Ribonucleic acid
RNA
Vertebrates: endocrinology
Ubiquitin
Pancreatic hormone
insulin
Enzyme
Growth
phosphatidylinositol 3-kinase-Akt pathway
Insulin like growth factor 1
Glucocorticoid
Protein
3-methylhistidine
Atrophy
Ligases
Muscle
Phosphatidylinositol 3-kinase
glucocorticoids
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Summary:Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes ("atrogenes"). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins. [PUBLICATION ABSTRACT]
ISSN:0193-1849
1522-1555