TitleInsulin fails to enhance mTOR phosphorylation, mitochondrial protein synthesis, and ATP production in human skeletal muscle without amino acid replacement.
Publication TypeJournal Article
Year of Publication2012
AuthorsBarazzoni, R, Short, KR, Asmann, Y, Coenen-Schimke, JM, Robinson, MM, K Nair, S
JournalAm J Physiol Endocrinol Metab
Date Published2012 Nov 01
KeywordsAdenosine Triphosphate, Adult, Amino Acids, Carbon Isotopes, Female, Gene Expression Regulation, Humans, Hyperinsulinism, Infusions, Intravenous, Insulin, Insulin, Regular, Human, Leucine, Male, Mitochondria, Muscle, Mitochondrial Proteins, Muscle, Skeletal, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, RNA, Messenger, TOR Serine-Threonine Kinases, Young Adult

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.

Alternate JournalAm. J. Physiol. Endocrinol. Metab.
PubMed ID22967500
PubMed Central IDPMC3492854
Grant ListR01 DK041973 / DK / NIDDK NIH HHS / United States
R01 DK-41973 / DK / NIDDK NIH HHS / United States
T32 DK-07352 / DK / NIDDK NIH HHS / United States
UL1 TR-00135 / TR / NCATS NIH HHS / United States