Mechanisms for increased insulin-stimulated Akt phosphorylation and glucose uptake in fast- and slow-twitch skeletal muscles of calorie-restricted rats.

  • Sharma N
  • Arias E
  • Bhat A
 et al. 
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Calorie restriction [CR; ~65% of ad libitum (AL) intake] improves insulin-stimulated glucose uptake (GU) and Akt phosphorylation in skeletal muscle. We aimed to elucidate the effects of CR on 1) processes that regulate Akt phosphorylation [insulin receptor (IR) tyrosine phosphorylation, IR substrate 1-phosphatidylinositol 3-kinase (IRS-PI3K) activity, and Akt binding to regulatory proteins (heat shock protein 90, Appl1, protein phosphatase 2A)]; 2) Akt substrate of 160-kDa (AS160) phosphorylation on key phosphorylation sites; and 3) atypical PKC (aPKC) activity. Isolated epitrochlearis (fast-twitch) and soleus (slow-twitch) muscles from AL or CR (6 mo duration) 9-mo-old male F344BN rats were incubated with 0, 1.2, or 30 nM insulin and 2-deoxy-[(3)H]glucose. Some CR effects were independent of insulin dose or muscle type: CR caused activation of Akt (Thr(308) and Ser(473)) and GU in both muscles at both insulin doses without CR effects on IRS1-PI3K, Akt-PP2A, or Akt-Appl1. Several muscle- and insulin dose-specific CR effects were revealed. Akt-HSP90 binding was increased in the epitrochlearis; AS160 phosphorylation (Ser(588) and Thr(642)) was greater for CR epitrochlearis at 1.2 nM insulin; and IR phosphorylation and aPKC activity were greater for CR in both muscles with 30 nM insulin. On the basis of these data, our working hypothesis for improved insulin-stimulated GU with CR is as follows: 1) elevated Akt phosphorylation is fundamental, regardless of muscle or insulin dose; 2) altered Akt binding to regulatory proteins (HSP90 and unidentified Akt partners) is involved in the effects of CR on Akt phosphorylation; 3) Akt effects on GU depend on muscle- and insulin dose-specific elevation in phosphorylation of Akt substrates, including, but not limited to, AS160; and 4) greater IR phosphorylation and aPKC activity may contribute at higher insulin doses.

Author-supplied keywords

  • Adenylate Kinase
  • Adenylate Kinase: metabolism
  • Animals
  • Blotting, Western
  • Body Weight
  • Body Weight: physiology
  • Caloric Restriction
  • Deoxyglucose
  • Deoxyglucose: metabolism
  • Eating
  • Eating: physiology
  • Glucose
  • Glucose Transporter Type 4
  • Glucose Transporter Type 4: metabolism
  • Glucose: metabolism
  • Hypoglycemic Agents
  • Hypoglycemic Agents: pharmacology
  • Immunoprecipitation
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin Receptor Substrate Proteins: metabolism
  • Insulin: pharmacology
  • Muscle Fibers, Fast-Twitch
  • Muscle Fibers, Fast-Twitch: drug effects
  • Muscle Fibers, Fast-Twitch: metabolism
  • Muscle Fibers, Slow-Twitch
  • Muscle Fibers, Slow-Twitch: drug effects
  • Muscle Fibers, Slow-Twitch: metabolism
  • Oncogene Protein v-akt
  • Oncogene Protein v-akt: metabolism
  • Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 3-Kinases: metabolism
  • Phosphorylation
  • Phosphorylation: drug effects
  • Proteins
  • Proteins: metabolism
  • Rats

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  • Naveen Sharma

  • Edward B Arias

  • Abhijit D Bhat

  • Donel a Sequea

  • Steve Ho

  • Kelsey K Croff

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