Disruption of the Striated Muscle Glycogen Targeting Subunit PPP1R3A of Protein Phosphatase 1 Leads to Increased Weight Gain, Fat Deposition, and Development of Insulin Resistance

Delibegović, Mirela; Armstrong, Christopher G.; Dobbie, Lorraine; Watt, Peter; Smith, Andrew J.H.; Cohen, Patricia T.W.

doi:10.2337/diabetes.52.3.596

Cited by 74 publications

(85 citation statements)

References 47 publications

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“…Several enzymes involved in glucose and glycogen metabolism were upregulated after vibration therapy (Table II). We observed increased expression of the phosphoinositide-3-kinase, regulatory subunit, polypeptide 3 (PIK3R3) gene that encodes a binding protein in the insulin-dependent pathway leading to inhibition of glycogen synthase kinase-3 (GSK-3), and that thus mediates net dephosphorylation of glycogen synthase (GS), with concomitant activation of the glycogen pathway (25). It is important to remember that PI3kinase functions upstream to Akt, a signaling factor very relevant to muscle hypertrophy mechanisms (26).…”

Section: Resultsmentioning

confidence: 99%

“…It is important to remember that PI3kinase functions upstream to Akt, a signaling factor very relevant to muscle hypertrophy mechanisms (26). Moreover, protein phosphatase regulatory subunits 3A and 3C (PPP1R 3A and 3C), genes encoding key enzymes for glycogen conservation in muscle (25), were upregulated. Another gene showing enhanced expression was dihydrolipoamide dehydrogenase, E3 complex of pyruvate dehydrogenase complex (DLD), a protein of the pyruvate dehydrogenase complex that transforms pyruvate into acetylcoenzyme A.…”

Section: Resultsmentioning

confidence: 99%

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Effects of local vibrations on skeletal muscle trophism in elderly people: mechanical, cellular, and molecular events

Pietrangelo¹

2009

Int J Mol Med

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Abstract. Several studies have examined the effects of vibrations on muscle mass and performance in young healthy people. We studied the effects of vibrations on muscles of elderly male and female volunteers (65-85 years of age) diagnosed with sarcopenia. We applied mechanical vibrations locally (local vibrational training) to the thigh muscles at 300 Hz for a period of 12 weeks, starting with a session of 15 min stimulation once a week and increasing to three sessions of 15 min per week. Treated muscles displayed enhanced maximal isometric strength and increased content of fast MyHC-2X myosin. Single muscle fiber analysis did not show any change in cross-sectional area or in specific tension. Analysis of transcriptional profiles by microarray revealed changes in gene expression after 12 weeks of local vibrational training. In particular, pathways related with energy metabolism, sarcomeric protein balance and oxidative stress response were affected. We conclude that vibration treatment is effective in counteracting the loss of muscular strength associated with sarcopenia and the mode of action of vibration is based on cellular and molecular changes which do not include increase in fiber or muscle size.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Effects of local vibrations on skeletal muscle trophism in elderly people: mechanical, cellular, and molecular events

Pietrangelo¹

2009

Int J Mol Med

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“…Glycogen levels in mouse muscle have also been manipulated via type 1 protein phosphatase subunits that target the enzyme to glycogen. Two reports (8,33) describe disruption of the gene encoding R GL or G M , which is expressed only in striated muscle, with conflicting results. In both cases, loss of R GL results in reduced muscle glycogen synthase activity and glycogen.…”

Section: Discussionmentioning

confidence: 99%

“…Suzuki et al (8) found no change in body weight, in vitro insulin-stimulated glucose uptake, or glucose tolerance as judged by GTT in three independently generated lines. Delibegovic et al (2003) reported that the null mice had increased fat mass upon aging and developed glucose intolerance in a GTT (33). The latter study depended on a single embryonic stem cell line.…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

et al. 2005

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Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5-10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals accumulated significantly higher levels of liver glycogen as compared with wild-type littermates. Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle. Diabetes 54: 3466 -3473, 2005 A fter a meal, glucose is distributed into various tissues of the body where it can be utilized as an energy source or stored as glycogen (1). Glycogen is a branched polymer of glucose residues connected by ␣-1,4-glycosidic linkages formed by the enzyme glycogen synthase (EC 2.4.1.11) and branchpoints formed via ␣-1,6-glycosidic linkages, introduced by the branching enzyme (EC 2.4.1.18). There are two mammalian isoforms of glycogen synthase. One, encoded by the GYS2 gene, appears to be expressed only in liver (2) while a second gene, GYS1, is expressed in skeletal and cardiac muscle as well as adipose tissue, kidney, and brain (3).Estimates of the contribution of skeletal muscle glycogen to glucose disposal after ingestion of carbohydrate vary. In humans, reports of ingested glucose conversion to muscle glycogen range from ϳ40% (4) up to 90% (5). It is widely accepted that muscle is an important site for glucose disposal and one might hypothesize that, in the absence of muscle glycogen, glucose clearance would be impaired. Consistent with this hypothesis, mutations in the GYS1 gene in humans have been implicated in certain diabetic populations with, for example, the Pro442Ala mutation resulting in decreased muscle glycogen synthase activity (6).We recently described the MGSKO mouse, in which the GYS1 gene is disrupted (7). Analysis of MGSKO mice confirmed the long-held supposition that glycogen synthase is required for glycogen synthesis since these animals were devoid of glycogen in cardiac and skeletal muscle (7). In the present study, we analyzed a number of metabolic parameters in the MGSKO mouse, including whole-body glucose metabolism, with an initial hypothesis that mice lacking the ability to synthesize muscl...

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“…Therefore, the PPARy2 polymorphism protects individuals from insulin insensitivity by promoting better suppression of lipid oxidation leading to more glucose disposal in males but not females. Another example is the 3' untranslated region of the PPP1R3A gene, a gene involved in glycogen synthase activity and associated with development of type 2 diabetes (9). Males homozygous for the polymorphism of PPP1R3A gene are significantly younger at diagnosis than female carriers (10).…”

Section: Sex Differences In Genetic Polymorphisms On the Development mentioning

confidence: 99%

Sex Differences in Obesity-Related Glucose Intolerance and Insulin Resistance

Shi¹,

Kumar²

2012

Glucose Tolerance

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Disruption of the Striated Muscle Glycogen Targeting Subunit PPP1R3A of Protein Phosphatase 1 Leads to Increased Weight Gain, Fat Deposition, and Development of Insulin Resistance

Cited by 74 publications

References 47 publications

Effects of local vibrations on skeletal muscle trophism in elderly people: mechanical, cellular, and molecular events

Effects of local vibrations on skeletal muscle trophism in elderly people: mechanical, cellular, and molecular events

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

Sex Differences in Obesity-Related Glucose Intolerance and Insulin Resistance

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