Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

Smith, Robert L.; Solberg, Rigmor; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild C.; Thoresen, G. Hege; Johansen, Harald Thidemann

doi:10.1371/journal.pone.0085721

Cited by 24 publications

(29 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It seems however that this is not the only mechanism of toxicity, and some authors propose other ways which would also be involved in geranylgeranyl pyrophosphate, cell apoptosis and dysfunction in glucose oxidation [49,50] . Some studies have linked this muscular toxicity with muscle weakness [51,52] .…”

Section: Statinsmentioning

confidence: 99%

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

Campins

Camps²,

Riera³

et al. 2016

Pharmacology

View full text Add to dashboard Cite

Sarcopenia is a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass and function. Reported prevalence of this geriatric syndrome, differs depending on the definition, the population and the method used to identify sarcopenia. The causes of sarcopenia are multifactorial, and can include genetic influence, immobility or disuse, endocrine factors, inflammation and nutritional deficiencies. These disorders involve an imbalance between anabolic and catabolic pathways that rules muscle mass. Many drugs taken regularly for common conditions may interact with some mechanisms that can alter the balance between protein synthesis and degradation. This may lead to a harmful or a beneficial effect on muscle mass and strength. Widely prescribed drugs could play an important role during the time of onset and development of sarcopenia. In this paper, we reviewed the current understanding of how can drugs contribute positively or negatively on sarcopenia and muscle wasting. We decided to focus this review on oral common drugs, which are usually prescribed in older adults, leaving aside other drugs as hormone therapy.

show abstract

Section: Statinsmentioning

confidence: 99%

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

Campins

Camps²,

Riera³

et al. 2016

Pharmacology

View full text Add to dashboard Cite

show abstract

“…Statins were shown to inhibit GLUT4 expression and glucose uptake in adipocytes [9][10][11][12]. In muscle cells, simvastatin was also reported to decrease glucose uptake [13,14], but no change in GLUT4 protein expression was observed [28].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3β phosphorylation

Yaluri

Modi

Kokkola

2016

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used for the treatment of hypercholesterolemia. Recent data indicates that simvastatin increases the risk of new-onset diabetes by impairing both insulin secretion and insulin sensitivity. However, systematic evaluation of mechanistic pathways is lacking. We aimed to explore the effects of simvastatin on glucose uptake and underlying mechanisms using L6 skeletal muscle myotubes. We performed our experiments at basal and insulin-stimulated conditions, at normal (5.5 mM) and high (16.7 mM) glucose. We showed that simvastatin inhibited glucose uptake at all conditions. We also found out that pravastatin, another widely used statin with different physicochemical properties, did not inhibit glucose uptake. The effect of simvastatin was reversed with geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate, implying that reduced protein geranylgeranylation has a role in simvastatin-induced insulin resistance. Simvastatin also decreased phosphorylation of insulin receptor (IR), insulin receptor substrate 1 (IRS-1), AKT and glycogen synthase kinase 3β (GSK-3β), and downregulated GLUT4. In conclusion, our data indicate that simvastatin decreased both basal and insulin-stimulated glucose uptake through inhibiting the critical steps in IR/IRS-1/AKT signaling cascade, and by hindering GLUT4 function and normal regulation of glycogen synthesis, contributing to insulin resistance.

show abstract

“…Caveolin‐1, a scaffolding protein and the principal component of the caveolae , affects hepatic lipid homeostasis . A recent study showed that treatment with simvastatin, a HMG‐CoA reductase inhibitor, decreased the mature form and activity of legumain . Moreover, we showed that knockdown of AACS in the liver of mice lowers the serum cholesterol concentration .…”

Section: Discussionmentioning

confidence: 61%

Site‐specific cleavage of acetoacetyl‐CoA synthetase by legumain

et al. 2016

View full text Add to dashboard Cite

Acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme and is responsible for the synthesis of cholesterol and fatty acids. We have previously shown that AACS is cleaved by legumain, a lysosomal asparaginyl endopeptidase. In this study, we attempted to determine the cleavage site of AACS. Mutagenesis analysis of AACS revealed that Asn547 is the specific cleavage site of AACS in mouse livers. The cleaved form of AACS (1-547) lost the ability to convert acetoacetate to acetoacetyl-CoA. Moreover, hydrodynamicsbased gene transduction showed that overexpression of AACS (1-547) increases the protein expression of caveolin-1, the principal component of the caveolae. These results suggest that cleavage of AACS by legumain is critical for the regulation of enzymatic activity and results in gain-of-function changes.

show abstract

Simvastatin Inhibits Glucose Metabolism and Legumain Activity in Human Myotubes

Cited by 24 publications

References 49 publications

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

Simvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3β phosphorylation

Site‐specific cleavage of acetoacetyl‐CoA synthetase by legumain

Contact Info

Product

Resources

About