Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways.
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.
Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Center for Life Sciences, CLS-16020, 3 Blackfan Circle, Boston, MA 02115, USA.
Yun Chau
YC
Long
Zhiyong
Z
Cheng
Kyle D
KD
Copps
Morris F
MF
White
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size; D009928:Organ Specificity; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
D051858:Forkhead Transcription Factors; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019344:Lactic Acid; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose