Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents

Authors


J. E. Mallinson: School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.  Email: joanne.mallinson@nottingham.ac.uk

Key points

  • • Statin myopathy impairs phosphatidylinositol 3-kinase/Akt signalling and activates forkhead box protein O (FOXO) transcription factors in vivo in rodent skeletal muscle. This is associated with upregulation of downstream gene targets known to increase proteasomal and lysosomal-mediated protein breakdown, oxidative stress and inflammation, and inhibit muscle carbohydrate (CHO) oxidation.
  • • We hypothesised that forcibly increasing muscle CHO oxidation in vivo, using the pyruvate dehydrogenase complex activator, dichloroacetate (DCA), would blunt statin-mediated increases in mRNA expression of these FOXO gene targets, thereby reducing statin myopathy.
  • • Chronic administration of DCA with simvastatin dampened statin-mediated increases in muscle atrophy F-box (MAFbx), cathepsin-L and pyruvate dehydrogenase kinase-4 mRNA in a dose-dependent manner, which was corroborated by protein activity and expression measurements, and blunted statin myopathy.
  • • These results provide convincing evidence that pharmacologically increasing muscle CHO oxidation reduces simvastatin-induced myopathy by dampening the upregulation of genes known to increase proteasomal and lysosomal protein breakdown and inhibit CHO oxidation.

Abstract  We previously reported that statin myopathy is associated with impaired carbohydrate (CHO) oxidation in fast-twitch rodent skeletal muscle, which we hypothesised occurred as a result of forkhead box protein O1 (FOXO1) mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) gene transcription. Upregulation of FOXO gene targets known to regulate proteasomal and lysosomal muscle protein breakdown was also evident. We hypothesised that increasing CHO oxidation in vivo, using the pyruvate dehydrogenase complex (PDC) activator, dichloroacetate (DCA), would blunt activation of FOXO gene targets and reduce statin myopathy. Female Wistar Hanover rats were dosed daily for 12 days (oral gavage) with either vehicle (control, 0.5% w/v hydroxypropyl-methylcellulose 0.1% w/v polysorbate-80; = 9), 88 mg kg−1 day−1 simvastatin (= 8), 88 mg kg−1 day−1 simvastatin + 30 mg kg−1 day−1 DCA (= 9) or 88 mg kg−1 day−1 simvastatin + 40 mg kg−1 day−1 DCA (= 9). Compared with control, simvastatin reduced body mass gain and food intake, increased muscle fibre necrosis, plasma creatine kinase levels, muscle PDK4, muscle atrophy F-box (MAFbx) and cathepsin-L mRNA expression, increased PDK4 protein expression, and proteasome and cathepsin-L activity, and reduced muscle PDC activity. Simvastatin with DCA maintained body mass gain and food intake, abrogated the myopathy, decreased muscle PDK4 mRNA and protein, MAFbx and cathepsin-L mRNA, increased activity of PDC and reduced proteasome activity compared with simvastatin. PDC activation abolished statin myopathy in rodent skeletal muscle, which occurred at least in part via inhibition of FOXO-mediated transcription of genes regulating muscle CHO utilisation and protein breakdown.

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