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Pharmacologically activating the pyruvate dehydrogenase complex protects against statin‐induced myopathy in rodent muscle
Author(s) -
Mallinson Joanne,
ConstantinTeodosiu Dumitru,
Sidaway James,
Westwood Russell,
Glaves Phillip,
Martin Elizabeth,
Davies Wendy,
Greenhaff Paul
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1051.12
Subject(s) - pdk4 , endocrinology , medicine , foxo1 , protein kinase b , phosphorylation , myopathy , chemistry , downregulation and upregulation , cathepsin , cathepsin l , skeletal muscle , pyruvate dehydrogenase complex , biology , biochemistry , enzyme , gene
Statin myopathy decreases Akt and FOXO phosphorylation, increases mRNA expression of FOXO gene targets PDK4, MAFbx and cathepsin‐L and reduces muscle glycogen use in rodent skeletal muscle (Mallinson et al 2009). We hypothesised that increasing carbohydrate flux by pharmacologically activating the pyruvate dehydrogenase complex (PDC) would reduce statin myopathy by increasing Akt phosphorylation and thereby blunting the upregulation of FOXO gene targets. Female Wistar Hanover rats were administered (oral gavage) vehicle (CON, n =9), 88 mg.kg −1. d −1 simvastatin (SIM, n =8) or 88 mg.kg −1. d −1 simvastatin and 40 mg.kg −1. d −1 DCA (SIM+DCA, n =9) for 12 d, after which the biceps muscle was collected. Compared to CON, SIM increased fibre necrosis and plasma CK levels ( p <0.05) and reduced PDC activity ( p <0.05), Akt ( p <0.05) and FOXO1 ( p <0.05) phosphorylation. MAFbx ( p <0.001), cathepsin‐L ( p <0.001) and PDK4 ( p <0.01) mRNA, were also elevated along with proteasome activity ( p <0.05). SIM+DCA markedly reduced fibre necrosis and plasma CK concentration ( p <0.01), whilst concomitantly increasing PDC activity ( p <0.05) and decreasing MAFbx ( p <0.001), cathepsin‐L ( p <0.001) and PDK4 ( p <0.01) mRNA expression and proteasome activity ( p =0.08). PDC activation reduced statin myopathy and catabolic gene expression, but independently of statin mediated reductions in Akt and FOXO1 phosphorylation.