Valproic Acid Activates the PI3K/Akt/mTOR Pathway in Muscle and Ameliorates Pathology in a Mouse Model of Duchenne Muscular Dystrophy

Gurpur, Praveen B.; Liu, Jianming; Burkin, Dean J.; Kaufman, Stephen J.

doi:10.2353/ajpath.2009.080537

Cited by 63 publications

(66 citation statements)

References 28 publications

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“…Our results indicate that mTOR signaling is also activated in tissues of the CB, PFC and HC in VPA-induced ASD rats. This result is consistent with Gurpur's report on VPA-exposed muscle (Gurpur et al, 2009) and different from the finding from Nicolini's study (Nicolini et al, 2015). In Nicolini's study, the tissue of fusiform gyrus from human brain and the lateral temporal neocortices from VPA-exposed rats was used to examine the activation of mTOR signaling.…”

Section: Discussionsupporting

confidence: 84%

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Qin

Dai

Yin

2016

Molecular and Cellular Neuroscience

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Section: Discussionsupporting

confidence: 84%

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Qin

Dai

Yin

2016

Molecular and Cellular Neuroscience

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“…In that study, Ribeiro et al (48) found that altered regulation of integrin trafficking in mtm-deficient flies was linked to muscle attachment and maintenance defects that are remarkably similar to those observed in XLMTM disease. This observation is especially intriguing in light of our finding that myotubularin regulates Akt signaling because disruption of integrin trafficking has previously been linked to impaired Akt signaling, pro-apoptotic signaling, and skeletal muscle atrophy (49,50). In addition, PIK3C2B has also been shown to regulate integrin trafficking and inhibit Akt phosphorylation in mammalian cells (51).…”

Section: Discussionmentioning

confidence: 96%

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Razidlo¹,

Katafiasz²,

Taylor

2011

Journal of Biological Chemistry

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Myotubularin is a 3-phosphoinositide phosphatase that is mutated in X-linked myotubular myopathy, a severe neonatal disorder in which skeletal muscle development and/or regeneration is impaired. In this report we provide evidence that siRNA-mediated silencing of myotubularin expression markedly inhibits growth factor-stimulated Akt phosphorylation, leading to activation of caspase-dependent pro-apoptotic signaling in HeLa cells and primary human skeletal muscle myotubes. Myotubularin silencing also inhibits Akt-dependent signaling through the mammalian target of rapamycin complex 1 as assessed by p70 S6-kinase and 4E-BP1 phosphorylation. Similarly, phosphorylation of FoxO transcription factors is also significantly reduced in myotubularin-deficient cells. Our data further suggest that inhibition of Akt activation and downstream survival signaling in myotubularin-deficient cells is caused by accumulation of the MTMR substrate lipid phosphatidylinositol 3-phosphate generated from the type II phosphatidylinositol 3-kinase PIK3C2B. Our findings are significant because they suggest that myotubularin regulates Akt activation via a cellular pool of phosphatidylinositol 3-phosphate that is distinct from that generated by the type III phosphatidylinositol 3-kinase hVps34. Because impaired Akt signaling has been tightly linked to skeletal muscle atrophy, we hypothesize that loss of Akt-dependent growth/survival cues due to impaired myotubularin function may be a critical factor underlying the severe skeletal muscle atrophy characteristic of muscle fibers in patients with X-linked myotubular myopathy.Myotubularin is the archetypical member of a family of phosphoinositide 3-phosphatases. Mutations in the myotubularin gene are causative for X-linked recessive myotubular myopathy (XLMTM), 4 also known as "centronuclear myopathy." XLMTM is a severe neonatal disorder in which the maturation and/or regeneration of skeletal muscle fibers is compromised (1, 2). Myofibers from affected individuals display abnormal centrally located nuclei and are severely atrophic. Mice in which the myotubularin gene has been deleted exhibit a skeletal muscle phenotype consistent with that of XLMTM disease. Like XLMTM patients, early stages of myogenesis in these mice appear to occur normally, and it has been suggested that skeletal muscle maintenance or regeneration is affected rather than early myogenic differentiation (3). Mutations in two other MTMR family proteins, MTMR2 and MTMR13, are causative for the demyelinating peripheral neuropathy type 4B Charcot-Marie-Tooth disease (4 -6).The myotubularin-related protein (MTMR) family consists of 14 proteins including 8 catalytically active lipid phosphatases and 6 forms that are inactive due to germ-line substitutions of essential catalytic residues (7). Active MTMRs specifically remove the 3-phosphate moiety from phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ), generating phosphatidylinositol (PI) and phosphatidylinositol 5-phosphate (PI(5)P), respectively (...

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“…Activation of Akt signaling promotes skeletal muscle hypertrophy (21)(22)(23), functioning through multiple signaling proteins involved in both survival and apoptotic pathways in skeletal muscle (24). Akt also protects cells from apoptosis by stimulating glucose transport in the cells and the recruitment of hexokinases to mitochondria (62).…”

Section: Discussionmentioning

confidence: 99%

Testosterone Supplementation Reverses Sarcopenia in Aging through Regulation of Myostatin, c-Jun NH2-Terminal Kinase, Notch, and Akt Signaling Pathways

et al. 2010

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Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n ϭ 15/ group). Young and old mice (n ϭ 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P Ͻ 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH 2 -terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway. (Endocrinology 151: 628 -638, 2010) S arcopenia is defined as the progressive decline of skeletal muscle mass and strength, which occurs with aging (1, 2). The rate of muscle loss is estimated to be 1-2% per year after the age of 50 yr and can affect even healthy physically active adults. Secondary to loss of skeletal muscle mass, there is a corollary decrease in functional independence and the ability to perform activities of daily living within the elderly population (2). Approximately 25% of people above the age of 70 yr and 40% of those who have reached the age of 80 yr are clinically sarcopenic (2, 3). Additionally, aging-associated skeletal muscle loss also leads to an increased risk of falls, fractures, dependency, and all-cause mortality (3-5).Mechanisms that regulate age-related loss of skeletal muscle mass are not well defined, but the pathogenesis is likely multifactorial. With age, in a process similar to that

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Valproic Acid Activates the PI3K/Akt/mTOR Pathway in Muscle and Ameliorates Pathology in a Mouse Model of Duchenne Muscular Dystrophy

Cited by 63 publications

References 28 publications

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

Myotubularin Regulates Akt-dependent Survival Signaling via Phosphatidylinositol 3-Phosphate

Testosterone Supplementation Reverses Sarcopenia in Aging through Regulation of Myostatin, c-Jun NH2-Terminal Kinase, Notch, and Akt Signaling Pathways

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