title: Insulin fails to enhance mTOR phosphorylation, mitochondrial protein synthesis, and ATP production in human skeletal muscle without amino acid replacement.
abstract: Systemic insulin administration causes hypoaminoacidemia by inhibiting protein degradation, which may in turn inhibit muscle protein synthesis (PS). Insulin enhances muscle mitochondrial PS and ATP production when hypoaminoacidemia is prevented by exogenous amino acid (AA) replacement. We determined whether insulin would stimulate mitochondrial PS and ATP production in the absence of AA replacement. Using l-[1,2-¹³C]leucine as a tracer, we measured the fractional synthetic rate of mitochondrial as well as sarcoplasmic and mixed muscle proteins in 18 participants during sustained (7-h) insulin or saline infusion (n = 9 each). We also measured muscle ATP production, mitochondrial enzyme activities, mRNA levels of mitochondrial genes, and phosphorylation of signaling proteins regulating protein synthesis. The concentration of circulating essential AA decreased during insulin infusion. Mitochondrial, sarcoplasmic, and mixed muscle PS rates were also lower during insulin (2-7 h) than during saline infusions despite increased mRNA levels of selected mitochondrial genes. Under these conditions, insulin did not alter mitochondrial enzyme activities and ATP production. These effects were associated with enhanced phosphorylation of Akt but not of protein synthesis activators mTOR, p70(S6K), and 4EBP1. In conclusion, sustained physiological hyperinsulinemia without AA replacement did not stimulate PS of mixed muscle or protein subfractions and did not alter muscle mitochondrial ATP production in healthy humans. These results support that insulin and AA act in conjunction to stimulate muscle mitochondrial function and mitochondrial protein synthesis.
authors.affiliation: Endocrine Research Unit, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rocco
authors.initials: R
authors.lastname: Barazzoni
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Short
authors.forename: Yan
authors.initials: Y
authors.lastname: Asmann
authors.forename: Jill M
authors.initials: JM
authors.lastname: Coenen-Schimke
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Robinson
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D000596:Amino Acids / Q000008:administration & dosage / Q000378:metabolism*; D002247:Carbon Isotopes; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D061386:Insulin, Regular, Human / Q000008:administration & dosage; D007930:Leucine / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000596:Amino Acids; D002247:Carbon Isotopes; D007328:Insulin; D061386:Insulin, Regular, Human; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D007930:Leucine