Abstract
Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin II infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger-1 are upregulated in angiotensin II-infused WT, but not in IGF-1-transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II-induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiotensin II / administration & dosage*
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Animals
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Cachexia / chemically induced
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Cachexia / metabolism
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Cachexia / pathology
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Heart Failure / chemically induced
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Heart Failure / metabolism
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Heart Failure / pathology
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Male
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Mice
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Mice, Transgenic
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Muscle Proteins / metabolism
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Muscle, Skeletal / metabolism*
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Muscle, Skeletal / pathology
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Renin-Angiotensin System / physiology
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction* / drug effects
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Signal Transduction* / genetics
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TOR Serine-Threonine Kinases
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Tripartite Motif Proteins
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Ubiquitin-Protein Ligases / metabolism
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Vasoconstrictor Agents / administration & dosage*
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Wasting Syndrome / chemically induced
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Wasting Syndrome / metabolism*
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Wasting Syndrome / pathology
Substances
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Muscle Proteins
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Proto-Oncogene Proteins
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Tripartite Motif Proteins
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Vasoconstrictor Agents
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Angiotensin II
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Insulin-Like Growth Factor I
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Fbxo32 protein, mouse
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Fbxo32 protein, rat
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SKP Cullin F-Box Protein Ligases
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TRIM63 protein, human
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Trim63 protein, mouse
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Trim63 protein, rat
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Ubiquitin-Protein Ligases
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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mTOR protein, rat
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases