Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways
Open Access
- 1 February 2011
- journal article
- research article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 31 (3), 430-441
- https://doi.org/10.1128/mcb.00983-10
Abstract
Coordination of skeletal muscle growth and metabolism with nutrient availability is critical for metabolic homeostasis. To establish the role of insulin-like signaling in this process, we used muscle creatine kinase (MCK)-Cre to disrupt expression of insulin receptor substrates Irs1 and Irs2 in mouse skeletal/cardiac muscle. In 2-week-old mice, skeletal muscle masses and insulin responses were slightly affected by Irs1, but not Irs2, deficiency. In contrast, the combined deficiency of Irs1 and Irs2 (MDKO mice) severely reduced skeletal muscle growth and Akt→mTOR signaling and caused death by 3 weeks of age. Autopsy of MDKO mice revealed dilated cardiomyopathy, reflecting the known requirement of insulin-like signaling for cardiac function (P. G. Laustsen et al., Mol. Cell. Biol. 27:1649-1664, 2007). Impaired growth and function of MDKO skeletal muscle were accompanied by increased Foxo-dependent atrogene expression and amino acid release. MDKO mice were resistant to injected insulin, and their isolated skeletal muscles showed decreased insulin-stimulated glucose uptake. Glucose utilization in MDKO mice and isolated skeletal muscles was shifted from oxidation to lactate production, accompanied by an elevated AMP/ATP ratio that increased AMP-activated protein kinase (AMPK)→acetyl coenzyme A carboxylase (ACC) phosphorylation and fatty acid oxidation. Thus, insulin-like signaling via Irs1/2 is essential to terminate skeletal muscle catabolic/fasting pathways in the presence of adequate nutrition.Keywords
This publication has 63 references indexed in Scilit:
- Irs1 Serine 307 Promotes Insulin Sensitivity in MiceCell Metabolism, 2010
- The Irs1 Branch of the Insulin Signaling Cascade Plays a Dominant Role in Hepatic Nutrient HomeostasisMolecular and Cellular Biology, 2009
- AMP‐activated Protein Kinase and FoxO Transcription Factors in Dietary Restriction–induced LongevityAnnals of the New York Academy of Sciences, 2009
- Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth RegulationCell Metabolism, 2008
- The TSC1–TSC2 complex: a molecular switchboard controlling cell growthBiochemical Journal, 2008
- AMPK Phosphorylation of Raptor Mediates a Metabolic CheckpointMolecular Cell, 2008
- Mechanisms of Disease: using genetically altered mice to study concepts of type 2 diabetesNature Clinical Practice Endocrinology & Metabolism, 2008
- Muscle-Specific Deletion of Rictor Impairs Insulin-Stimulated Glucose Transport and Enhances Basal Glycogen Synthase ActivityMolecular and Cellular Biology, 2008
- The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndromeProceedings of the National Academy of Sciences of the United States of America, 2007
- Essential Role of Insulin and Insulin-Like Growth Factor 1 Receptor Signaling in Cardiac Development and FunctionMolecular and Cellular Biology, 2007