Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle

Rebalka, Irena A.; Raleigh, Matthew J.; Snook, Laelie A.; Rebalka, Alexandra N.; MacPherson, Rebecca E. K.; Wright, David C.; Schertzer, Jonathan D.; Hawke, Thomas J.

doi:10.3389/fendo.2016.00095

Cited by 4 publications

(4 citation statements)

References 21 publications

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“…Given information gleaned from previous work as well as this investigation, it is hypothesized that Fluvastatin is inhibiting myoblast fusion in vitro via a mechanism independent of extracellular matrix remodeling. Although further investigation into this mechanism are warranted, the current investigation complements previous reports of the negative effects of statins on skeletal muscle health, which include changes in the adaptive response to stressors (current work), storage, and transport of lipids (Rebalka et al, 2016 ), and metabolic capacity/glucose handling (Ridker et al, 2008 ; Duvnjak and Blaslov, 2016 ).…”

Section: Discussionsupporting

confidence: 70%

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

et al. 2017

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Those with diabetes invariably develop complications including cardiovascular disease (CVD). To reduce their CVD risk, diabetics are generally prescribed cholesterol-lowering 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors (i.e., statins). Statins inhibit cholesterol biosynthesis, but also reduce the synthesis of a number of mevalonate pathway intermediates, leading to several cholesterol-independent effects. One of the pleiotropic effects of statins is the reduction of the anti-fibrinolytic hormone plasminogen activator inhibitor-1 (PAI-1). We have previously demonstrated that a PAI-1 specific inhibitor alleviated diabetes-induced delays in skin and muscle repair. Here we tested if statin administration, through its pleiotropic effects on PAI-1, could improve skin and muscle repair in a diabetic rodent model. Six weeks after diabetes onset, adult male streptozotocin-induced diabetic (STZ), and WT mice were assigned to receive control chow or a diet enriched with 600 mg/kg Fluvastatin. Tibialis anterior muscles were injured via Cardiotoxin injection to induce skeletal muscle injury. Punch biopsies were administered on the dorsal scapular region to induce injury of skin. Twenty-four days after the onset of statin therapy (10 days post-injury), tissues were harvested and analyzed. PAI-1 levels were attenuated in statin-treated diabetic tissue when compared to control-treated tissue, however no differences were observed in non-diabetic tissue as a result of treatment. Muscle and skin repair were significantly attenuated in Fluvastatin-treated STZ-diabetic mice as demonstrated by larger wound areas, less mature granulation tissue, and an increased presence of smaller regenerating muscle fibers. Despite attenuating PAI-1 levels in diabetic tissue, Fluvastatin treatment impaired cutaneous healing and skeletal muscle repair in STZ-diabetic mice.

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Section: Discussionsupporting

confidence: 70%

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

et al. 2017

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“…Muscle fiber cross-sectional area was calculated from Ն200 individual fibers per H & E-stained TA muscle section. The number of myopathic fibers was also quantified from H & E-stained TA sections as the sum of the number of centrally located nuclei per millimeter squared and the number of necrotic fibers per millimeter squared within the entire TA muscle cross-sectional area, as we have published previously (26). Muscle fiber types in TA cross-sections were determined by immunofluorescence using primary antibodies for myosin heavy chain I, IIa, and IIb (Developmental Studies Hybridoma Bank, University of Iowa), as described (2).…”

Section: Animal Protocols All Procedures Were Approved By the Mcmastermentioning

confidence: 99%

The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice

McBride

Foley

D’Souza

et al. 2017

American Journal of Physiology-Endocrinology and Metabolism

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The mechanisms underpinning decreased skeletal muscle strength and slowing of movement during aging are ill-defined. "Inflammaging," increased inflammation with advancing age, may contribute to aspects of sarcopenia, but little is known about the participatory immune components. We discovered that aging was associated with increased caspase-1 activity in mouse skeletal muscle. We hypothesized that the caspase-1-containing NLRP3 inflammasome contributes to sarcopenia in mice. Male C57BL/6J wild-type (WT) and NLRP3 mice were aged to 10 (adult) and 24 mo (old). NLRP3 mice were protected from decreased muscle mass (relative to body mass) and decreased size of type IIB and IIA myofibers, which occurred between 10 and 24 mo of age in WT mice. Old NLRP3 mice also had increased relative muscle strength and endurance and were protected from age-related increases in the number of myopathic fibers. We found no evidence of age-related or NLRP3-dependent changes in markers of systemic inflammation. Increased caspase-1 activity was associated with GAPDH proteolysis and reduced GAPDH enzymatic activity in skeletal muscles from old WT mice. Aging did not alter caspase-1 activity, GAPDH proteolysis, or GAPDH activity in skeletal muscles of NLRP3 mice. Our results show that the NLRP3 inflammasome participates in age-related loss of muscle glycolytic potential. Deletion of NLRP3 mitigates both the decline in glycolytic myofiber size and the reduced activity of glycolytic enzymes in muscle during aging. We propose that the etiology of sarcopenia involves direct communication between immune responses and metabolic flux in skeletal muscle.

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“…Muscle symptoms, such as fatigue, pain or weakness, are the most common statin side effects: these symptoms occur in up to 7% of statin users and up to 25% of statin users who participate in vigorous physical exercise [19]. Previous studies have shown that statin-induced muscle dysfunction is related to impaired mitochondrial function [20–22], protein breakdown [23], reduced protein synthesis [24], decreased lipid uptake and synthesis [25] and increased ectopic lipid deposition [26]. Skeletal muscle accounts for the major glucose disposal site in the body, and impaired muscle viability or glucose uptake may result in a risk of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

et al. 2019

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Background HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs widely used to treat hypercholesterolemia and prevent cardiovascular disease. Statins are generally well tolerated, but adverse reactions may occur, particularly myopathy and new onset of diabetes. The exact mechanism of statin-induced myopathy and diabetes has not been fully elucidated. We have previously shown that treatment of hypercholesterolemic (LDLr −/− ) mice with pravastatin for 2 months decreased pancreatic islet insulin secretion and increased oxidative stress and cell death, but no glucose intolerance was observed. The purpose of the current work was to study long-term pravastatin effects on glucose homeostasis, insulin sensitivity, muscle protein turnover and cell viability. Methods LDLr −/− mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes. Results After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers (Bax protein and cleaved caspase-3) and augmented superoxide anion production. Conclusions In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.

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Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle

Cited by 4 publications

References 21 publications

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

Statin Therapy Negatively Impacts Skeletal Muscle Regeneration and Cutaneous Wound Repair in Type 1 Diabetic Mice

The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice

Diabetogenic effect of pravastatin is associated with insulin resistance and myotoxicity in hypercholesterolemic mice

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