Short-term Caloric Restriction Does Not Modify the In Vivo Insulin Signaling Pathway Leading to Akt Activation in Skeletal Muscle of Ames Dwarf (Prop1^df/Prop1^df) Mice

Abstract

The purpose of this study was to analyze the interaction between caloric restriction (CR) and the dwarf mutation at the level of insulin sensitivity and signal transduction. To this end, we analyzed the in vivo status of the insulin signaling system in skeletal muscle from Ames dwarf (df/df) and normal mice fed ad libitum or subjected to short-term (20-day) CR. We measured insulin-stimulated phosphorylation of the IR and IRS-1, IRS-1-p85 association and Akt activation, and the abundance of the IR, IRS-1, p85, GLUT-4 and IGF-1 receptor in skeletal muscle. In terms of glucose homeostasis, the response to CR was different in both groups of animals. In normal animals, CR induced a significant reduction in both circulating insulin and glucose levels, while CR did not modify these parameters in df/df mice. We did not find any significant alteration in either activation or abundance of signaling molecules analyzed after short-term CR in either normal or Ames dwarf mice. We conclude that the initial adaptation to CR in normal mice is an increase in insulin sensitivity without changes in insulin signal transduction, and that this adaptation is not evidenced in df/df mice, probably since they are already hypersensitive to insulin.

Key words

Aging - caloric restriction - growth hormone - IGF-1 - insulin receptor - IRS-1 - insulin sensitivity

References

• 1 Barger J L, Walford R L, Weindruch R. The retardation of aging by caloric restriction: its significance in the transgenic era.  Exp Gerontol. 2003;  38 1343-1351
• 2 Masoro E J. Caloric restriction and aging: an update.  Exp Gerontol. 2000;  35 299-305
• 3 Roth G S, Mattison J A, Ottinger M A, Chachich M E, Lane M A, Ingram D K. Aging in Rhesus Monkeys: Relevance to human health interventions.  Science. 2004;  305 1423-1425
• 4 Fontana L, Meyer E T, Klein S, Holloszy J O. Long term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.  Proc Natl Acad Sci USA. 2004;  101 6659-6663
• 5 Liang H, Masoro E J, Nelson J F, Strong R, McMahan C A, Richardson A. Genetic mouse models of extended lifespan.  Exp Gerontol. 2003;  38 1353-1364
• 6 Bartke A, Brown-Borg H, Mattison J, Kinney B, Hauck S, Wright C. Prolonged longevity of hypopituitary dwarf mice.  Exp Gerontol. 2001;  36 21-28
• 7 Dominici F P, Hauck S, Argentino D P, Bartke A, Turyn D. Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice.  J Endocrinol. 2002;  173 81-94
• 8 Bartke A, Wright J C, Mattison J A, Ingram D K, Miller R A, Roth G S. Extending the lifespan of long-lived mice.  Nature. 2001;  414 412-414
• 9 Barbieri M, Bonafé M, Franceschi C, Paolisso G. Insulin/IGF-1-signaling pathway: an evolutionary conserved mechanism of longevity from yeast to humans.  Am J Physiol. 2003;  285 E1064-E1071
• 10 Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals.  Science. 2003;  299 1346-1351
• 11 Richardson A, Liu F, Adamo M L, Remmen H V, Nelson J F. The role of insulin and insulin-like growth factor-I in mammalian ageing.  Best Pract Res Clin Endocrinol Metab. 2004;  18 393-406
• 12 White M F. Insulin signaling in health and disease.  Science. 2003;  302 1710-1711
• 13 Whiteman E L, Cho H, Birnbaum M J. Role of Akt/protein kinase B in metabolism.  Trends Endocrinol Metab. 2002;  13 444-451
• 14 Dominici F P, Argentino D P, Bartke A, Turyn D. The dwarf mutation decreases high dose insulin responses in skeletal muscle, the opposite of effects in liver.  Mech Ageing Dev. 2003;  124 819-827
• 15 Heilbronn L K, Ravussin E. Caloric restriction and aging: review of the literature and implications for studies in humans.  Am J Clin Nutr. 2003;  78 361-369
• 16 McCurdy C E, Davidson R T, Cartee G D. Brief calorie restriction increases Akt2 phosphorylation in insulin-stimulated rat skeletal muscle.  Am J Physiol. 2003;  285 E693-E700
• 17 Saltiel A R, Kahn C R. Insulin signaling and the regulation of glucose and lipid metabolism.  Nature. 2001;  414 799-806
• 18 Kausch C, Staiger H, Staiger K, Krützfeld J, Matthaei S, Häring H U, Stumvoll M. Skeletal muscle cells from insulin-resistant (non-diabetic) individuals are susceptible to insulin desensitization by palmitate.  Horm Metab Res. 2003;  35 570-576
• 19 Argentino D P, Dominici F P, Muñoz M C, Al-Regaiey K A, Bartke A, Turyn D. Effects of long-term caloric restriction on glucose homeostasis and on the first steps of the insulin signaling system in skeletal muscle of normal and Ames dwarf (Prop1/Prop1) mice.  Exp Gerontol. 2005;  40 27-35
• 20 Balage M, Grizard J, Manin M. Effect of caloric restriction on skeletal muscle and liver insulin binding in growing rat.  Horm Metab Res. 1990;  22 207-214
• 21 Balage M, Grizard J, Sornet C, Simon J, Dardevet D, Manin M. Insulin binding and receptor tyrosine kinase activity in rat liver and skeletal muscle: effect of starvation.  Metabolism. 1990;  39 366-373
• 22 Cecchin F, Ittoop O, Sinha M K, Caro J F. Insulin resistance in uremia: insulin receptor kinase activity in liver and muscle from chronic uremic rats.  Am J Physiol Endocrinol Metab. 1988;  254 E394-E401
• 23 Zhu M, Miura J, Lu L X, Bernier M, DeCabo R, Lane M A, Roth G S, Ingram D K. Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization.  Exp Gerontol. 2004;  39 1049-1059
• 24 Dean D J, Cartee G D. Caloric restriction increases insulin-stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 in rat skeletal muscle.  Acta Physiol Scand. 2000;  169 133-139
• 25 Dean D J, Brozinick J T, Cushman S W, Cartee G D. Caloric restriction increases cell surface GLUT-4 in insulin-stimulated skeletal muscle.  Am J Physiol. 1998;  275 E957-E964
• 26 Gazdag A C, Dumke C L, Kahn C R, Cartee G D. Caloric restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice.  Diabetes. 1999;  48 1930-1936
• 27 Davidson R T, Arias E B, Cartee G D. Caloric restriction increases muscle insulin action but not IRS-1-, IRS-2-, or phosphotyrosine-PI 3-kinase.  Am J Physiol. 2002;  282 E270-E276
• 28 Miller R A, Chang Y, Galecki A T, Al-Regaiey K A, Kopchick J J, Bartke A. Gene expression patterns in calorically restricted mice: partial overlap with long-lived mutant mice.  Mol Endocrinol. 2002;  16 2657-2666
• 29 Dominici F P, Cifone D, Bartke A, Turyn D. Alterations in early steps of the insulin-signaling system in skeletal muscle of GH- transgenic mice.  Am J Physiol. 1999;  277 E447-E454
• 30 Dean D J, Cartee G D. Brief dietary restriction increases skeletal muscle glucose transport in old Fischer 344 rats.  J Gerontol A Biol Sci Med Sci. 1996;  51 B208-B213
• 31 Kahn C R. Pathogenesis of type 2 non-insulin-dependent diabetes. In: Korenman S, Kahn CR (eds) Diabetes (Atlas of Clinical Endocrinology, 2). Blackwell Science Inc 1999: 71-82
• 32 Goren H J, Kulkarni R T, Kahn C R. Glucose homeostasis and tissue transcript content of insulin signaling intermediates in four inbred strains of mice: C57BL/6, C57BLKS/6, DBA/2 and 129X1.  Endocrinology. 2004;  145 3307-3323
• 33 Cartee G D, Kietzke E W, Briggs-Tung C. Adaptation of muscle glucose transport with caloric restriction in adult, middle-aged, and old rats.  Am J Physiol. 1994;  266 R1443-R1447
• 34 Bornfeld K E, Skottner A, Arqvist H J. In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-1 in rat muscle.  J Endocrinol. 1992;  135 203-211
• 35 Butler A A, Ambler G R, Breier B H, LeRoith D, Roberts C T Jr, Gluckman P D. Growth hormone (GH) and insulin-like growth factor-I (IGF-1) treatment of the GH-deficient dwarf rat: differential effects on IGF-1 transcription start site expression in hepatic and extrahepatic tissues and lack of effect on type I IGF receptor mRNA expression.  Mol Cell Endocrinol. 1994;  101 321-330
• 36 Eshet R, Werner H, Klinger B, Silbergeld A, Laron Z, LeRoith D, Roberts C T Jr. Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels.  J Mol Endocrinol. 1993;  10 115-120
• 37 D’Costa A P, Lenham J E, Ingram R L, Sonntag W E. Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats.  Mech Ageing Dev. 1993;  71 59-71
• 38 Hribal M L, Oriente F, Accili D. Mouse models of insulin resistance.  Am J Physiol Endocrinol Metab. 2002;  282 E977-E981