Insulin stimulation of muscle protein synthesis in obese Zucker rats is not via a rapamycin-sensitive pathway

Fluckey, James D.; Pohnert, Steven C.; Boyd, S. G.; Cortright, Ronald N.; Trappe, Todd A.; Dohm, G. Lynis

doi:10.1152/ajpendo.2000.279.1.e182

Cited by 25 publications

(32 citation statements)

References 25 publications

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“…The underlying molecular mechanisms for these alterations remain unclear. However, it is interesting to note that other studies have demonstrated that the phosphorylation of p70S6k in response to insulin (11,13,26) and increased muscle loading (19) may be altered in the diabetic rat model.…”

Section: Discussionmentioning

confidence: 97%

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

Katta

Kundla²,

Kakarla

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent data have suggested that insulin resistance may be associated with a diminished ability of skeletal muscle to undergo hypertrophy (Paturi S, Gutta AK, Kakarla SK, Katta A, Arnold EC, Wu M, Rice KM, Blough ER. J Appl Physiol 108: 7–13, 2010). Here we examine the effects of insulin resistance using the obese Zucker (OZ) rat with increased muscle loading on the regulation of the mammalian target of rapamycin (mTOR) and its downstream signaling intermediates 70-kDa ribosomal protein S6 kinase (p70S6k), ribosomal protein S6 (rpS6), eukaryotic elongation factor 2 (eEF2), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Compared with that observed in lean Zucker (LZ) rats, the degree of soleus muscle hypertrophy as assessed by changes in muscle wet weight (LZ: 35% vs. OZ: 16%) was significantly less in the OZ rats after 3 wk of muscle overload ( P < 0.05). This diminished growth in the OZ rats was accompanied by significant impairments in the ability of the soleus to undergo phosphorylation of mTOR (Ser2448), p70S6k (Thr389), rpS6 (Ser235/236), and protein kinase B (Akt) (Ser473 and Thr308) ( P < 0.05). Taken together, these data suggest that impaired overload-induced hypertrophy in insulin-resistant skeletal muscle may be related to decreases in the ability of the muscle to undergo mTOR-related signaling.

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Section: Discussionmentioning

confidence: 97%

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

Katta

Kundla²,

Kakarla

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Therefore, we sought to counter the harmful effects of obesity on skeletal muscle by treatment with a well-established AMPK agonist-mTOR antagonist that would not have the harmful lipotoxic side effect of rapamycin. Skeletal muscles that are dyslipidemic, type 2 diabetic, and/or obese are less responsive to growth-promoting stimuli (14,15,47). Previous data (18,23,39) show that obesity-related issues of dyslipidemia, glucose intolerance, and insulin insensitivity were improved with AICAR treatment.…”

Section: Discussionmentioning

confidence: 99%

AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle

Drake

Alway

Hollander

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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DL. AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R1546 -R1554, 2010. First published September 15, 2010 doi:10.1152/ajpregu.00337.2010.-The aim of this study was to determine the effect of 14 days of 5-aminoimidazole-4-carboxamide-1␤-4-ribofuranoside (AICAR) treatment on mammalian target of rapamycin (mTOR) signaling and mTOR-regulated processes (i.e., translation initiation) in obese mouse skeletal muscle. Our hypothesis was that daily treatment (14 days) with AICAR would normalize obesity-induced alterations in skeletal muscle mTOR signaling and mTOR-regulated processes to lean levels and positively affect muscle mass. Fourteen-week-old male, lean (L; 31.3 g body wt) wild-type and ob/ob (O; 59.6 g body wt) mice were injected with the AMP-activated kinase (AMPK) activator AICAR (A) at 0.5 mg · g body wt Ϫ1 · day Ϫ1 or saline control (C) for 14 days. At 24 h after the last injection (including a 12-h fast), all mice were killed, and the plantar flexor complex muscle (gastrocnemius, soleus, and plantaris) was excised for analysis. Muscle mass was lower in OC (159 Ϯ 12 mg) than LC, LA, and OA (176 Ϯ 10, 178 Ϯ 9, and 166 Ϯ 16 mg, respectively) mice, independent of a body weight change. A decrease in obese muscle mass corresponded with higher muscle cross section staining intensity for lipid and glycogen, higher blood glucose and insulin levels, and lower nuclear-enriched fractions for peroxisome proliferator-activated receptor-␥ coactivator-1␣ protein expression in OC skeletal muscle, which was normalized with AICAR treatment. AMPK and acetyl-cocarboxylase phosphorylation was reduced in OC mice and augmented by AICAR treatment in OA mice. Conversely, OC mice displayed higher activation of downstream targets (S6 kinase-1 and ribosomal protein S6) of mTOR and lower raptor-associated mTOR than LC mice, which were reciprocally altered after 14 days of AICAR treatment. Dysregulation of translational capacity was improved in OA mice, as assessed by sucrose density gradient fractionation of ribosomes, total and ribosome-associated RNA content, eukaryotic initiation factor 4F complex formation, and eukaryotic initiation factor 4G phosphorylation. These data show that short-term (14 days) AMPK agonist treatment augments regulatory processes in atrophic obese mouse skeletal muscle through the normalization of mTOR signaling and mRNA translation closer to lean levels.

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“…Furthermore, insulin has been demonstrated to be a necessary component of muscle protein synthesis after resistance exercise (9,14,15). Rapamycin was provided when necessary as an upstream inhibitor of mTOR, and we have been successful in inhibiting mTOR with rapamycin at this concentration (13). Rapamycin was used alone or together with insulin to determine the effect of mTOR signaling on the postexercise protein synthesis response.…”

Section: Animals and Operant Conditioningmentioning

confidence: 99%

Insulin facilitation of muscle protein synthesis following resistance exercise in hindlimb-suspended rats is independent of a rapamycin-sensitive pathway

Fluckey

Dupont‐Versteegden²,

Knox³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Hindlimb suspension (HS) results in rapid losses of muscle mass, which may in part be explained by attenuated rates of protein synthesis. Mammalian target of rapamycin (mTOR) regulates protein synthesis and has been implicated as a potential mediator of the muscle mass decrement with HS. This study examined the effect of resistance exercise, a muscle hypertrophy stimulant, on rates of protein synthesis after 4 days of HS in mature male Sprague-Dawley rats. Flywheel resistance exercise (2 sets x 25 repetitions) was conducted on days 2 and 4 of HS (HSRE). Sixteen hours after the last exercise bout, soleus muscles were assessed for in vitro rates of protein synthesis, with and without insulin (signaling agonist) and/or rapamycin (mTOR inhibitor). Results demonstrated that soleus mass was reduced (P < 0.05) with HS, but this loss of mass was not observed (P > 0.05) with HSRE. Muscle protein synthesis was diminished (P < 0.05) with HS, with or without insulin. HSRE also had reduced rates of synthesis without insulin; however, insulin administration yielded higher (P < 0.05) rates in HSRE compared with HS or control. Rapamycin diminished protein synthesis in all groups (P < 0.05), but insulin rescued synthesis rates in HS and HSRE to levels similar to insulin alone for each group, suggesting that alternate signaling pathways develop to increase protein synthesis with HS. These results demonstrate that the capacity for an augmented anabolic response to resistance exercise is maintained after 4 days of HS and is independent of a rapamycin-sensitive pathway.

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Insulin stimulation of muscle protein synthesis in obese Zucker rats is not via a rapamycin-sensitive pathway

Cited by 25 publications

References 25 publications

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle

Insulin facilitation of muscle protein synthesis following resistance exercise in hindlimb-suspended rats is independent of a rapamycin-sensitive pathway

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