A Limited Role for PI(3,4,5)P3 Regulation in Controlling Skeletal Muscle Mass in Response to Resistance Exercise

Division of Molecular Physiology, University of Dundee, Dundee, Scotland, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 07/2010; 5(7):e11624. DOI: 10.1371/journal.pone.0011624
Source: PubMed

ABSTRACT Since activation of the PI3K/(protein kinase B; PKB/akt) pathway has been shown to alter muscle mass and growth, the aim of this study was to determine whether resistance exercise increased insulin like growth factor (IGF) I/phosphoinositide 3-kinase (PI3K) signalling and whether altering PI(3,4,5)P(3) metabolism genetically would increase load induced muscle growth.
Acute and chronic resistance exercise in wild type and muscle specific PTEN knockout mice were used to address the role of PI(3,4,5)P(3) regulation in the development of skeletal muscle hypertrophy. Acute resistance exercise did not increase either IGF-1 receptor phosphorylation or IRS1/2 associated p85. Since insulin/IGF signalling to PI3K was unchanged, we next sought to determine whether inactivation of PTEN played a role in load-induced muscle growth. Muscle specific knockout of PTEN resulted in small but significant increases in heart (PTEN(+/+) = 5.00+/-0.02 mg/g, PTEN(-/-) = 5.50+/-0.09 mg/g), and TA (PTEN(+/+) = 1.74+/-0.04 mg/g, PTEN(-/-) = 1.89 +/-0.03) muscle mass, while the GTN, SOL, EDL and PLN remain unchanged. Following ablation, hypertrophy of the PLN, SOL or EDL muscles was similar between PTEN(-/-) and PTEN(+/+) animals. Even though there were some changes in overload-induced PKB and S6K1 phosphorylation, 1 hr following acute resistance exercise there was no difference in the phosphorylation state of S6K1 Thr389 between genotypes.
These data suggest that physiological loading does not lead to the enhanced activation of the PI3K/PKB/mTORC1 axis and that neither PI3K activation nor PTEN, and by extension PI(3,4,5)P(3) levels, play a significant role in adult skeletal muscle growth.

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Available from: Keith Baar, Sep 29, 2015
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    • "To induce EDL muscle overload, in a different set of animals, unilateral synergistic ablation of the tibialis anterior muscle was carried out as previously described (Rosenblatt and Parry 1992; Hamilton et al. 2010). The contralateral limb was submitted to sham surgery. "
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    ABSTRACT: The aim of this study was to evaluate the effect of overload-induced hypertrophy on extensor digitorum longus (EDL) and soleus muscles of streptozotocin-induced diabetic rats. The overload-induced hypertrophy and absolute tetanic and twitch forces increases in EDL and soleus muscles were not different between diabetic and control rats. Phospho-Akt and rpS6 contents were increased in EDL muscle after 7 days of overload and returned to the pre-overload values after 30 days. In the soleus muscle, the contents of total and phospho-Akt and total rpS6 were increased in both groups after 7 days. The contents of total Akt in controls and total rpS6 and phospho-Akt in the diabetic rats remained increased after 30 days. mRNA expression after 7 days of overload in the EDL muscle of control and diabetic animals showed an increase in MGF and follistatin and a decrease in myostatin and Axin2. The expression of FAK was increased and of MuRF-1 and atrogin-1 decreased only in the control group, whereas Ankrd2 expression was enhanced only in diabetic rats. In the soleus muscle caused similar changes in both groups: increase in FAK and MGF and decrease in Wnt7a, MuRF-1, atrogin-1, and myostatin. Differences between groups were observed only in the increased expression of follistatin in diabetic animals and decreased Ankrd2 expression in the control group. So, insulin deficiency does not impair the overload-induced hypertrophic response in soleus and EDL muscles. However, different mechanisms seem to be involved in the comparable hypertrophic responses of skeletal muscle in control and diabetic animals. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    07/2015; 3(7):16. DOI:10.14814/phy2.12457
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    • "Then fifteen BEH mice and eighteen BEH+/+ mice were subjected to the functional overload of Sol for 28 days starting at the age of 14 weeks. These animals were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg), and the gastrocnemius muscle (GAS) was surgically removed from a randomly selected leg using similar methods as described earlier (Hamilton et al., 2010). Mice were given buprenorphine after surgery for pain relief and were monitored on a daily basis. "
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    ABSTRACT: Myostatin dysfunction promotes muscle hypertrophy, which can complicate assessment of muscle properties. We examined force generating capacity and creatine kinase (CK) efflux from skeletal muscles of young mice before they reach adult body and muscle size. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles of Berlin high (BEH) mice with dysfunctional myostatin, i.e., homozygous for inactivating myostatin mutation, and with a wild-type myostatin (BEH+/+) were studied. The muscles of BEH mice showed faster (P < 0.01) twitch and tetanus contraction times compared with BEH+/+ mice, but only EDL displayed lower (P < 0.05) specific force. SOL and EDL of age-matched but not younger BEH mice showed greater exercise-induced CK efflux compared with BEH+/+ mice. In summary, myostatin dysfunction leads to impairment in muscle force generating capacity in EDL and increases susceptibility of SOL and EDL to protein loss after exercise.
    Applied Physiology Nutrition and Metabolism 04/2015; 40(8):150406143556003. DOI:10.1139/apnm-2014-0513 · 2.34 Impact Factor
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    • "In culture, high levels of mTORC1/S6K1 activity reduce IRS-1 protein and mRNA levels, diminish its function (16), and through serine phosphorylation targets it for proteasomal degradation (43). In vivo, 18 h of extremely high S6K1 phosphorylation [up to 80-fold (35)] and activity [up to 4-fold (27)] following acute resistance type contractions do not decrease total IRS-1 or -2 levels immunoprecipated from muscle lysate (15). However, here we show that a prolonged and relatively small increase in S6K1 phosphorylation (maximum of 4-fold) is associated with complete loss of IRS-1/2. "
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    ABSTRACT: The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supra-physiological model of hypertrophy. To achieve this, mTORC1-IRS1/2 signaling, BiP/CHOP/IRE1α, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of ~4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors were high throughout the 21d of overload. However, IGF signaling was limited since IRS1 and 2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS1/2 protein were paralleled by increases in GRB10(Ser501/503) and S6K1(Thr389) phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB(Ser473) phosphorylation was higher from 3-6 days and this was associated with increased TSC2(Thr939) phosphorylation. The phosphorylation of TSC2(Thr1345) (an AMPK site) was also elevated whereas phosphorylation at the other PKB site, Thr(1462), was unchanged at 6d. In agreement with the phosphorylation of Thr(1345), synergist ablation led to activation of α1-AMPK during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1α levels decreased. These data suggest that during supra-physiological muscle loading, at least three potential molecular brakes engage to down-regulate mTORC1.
    AJP Endocrinology and Metabolism 06/2014; 307(4). DOI:10.1152/ajpendo.00674.2013 · 3.79 Impact Factor
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