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

Abstract

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; n = 9), 88 mg kg −1 day −1 simvastatin (n = 8), 88 mg kg −1 day −1 simvastatin + 30 mg kg −1 day −1 DCA (n = 9) or 88 mg kg −1 day −1 simvastatin + 40 mg kg −1 day −1 DCA (n = 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.

Statin myalgia is not associated with reduced muscle strength, mass or protein turnover in older male volunteers, but is allied with a slowing of time to peak power output, insulin resistance and differential muscle mRNA expression

“…In keeping with the post‐absorptive leg protein breakdown responses and lack of difference in muscle mass between statin myalgia and control volunteers, the post‐prandial increase in muscle protein synthesis was not blunted in statin myalgia, and contrasts what might have been expected based on the disruption of PI3k/Akt signalling in rodent statin myopathy (Mallinson et al . , ). Indeed, statin myalgic subjects in the present study showed no inactivation of the anabolic signalling proteins, p70S6k (Fig.…”

“…This occurred, at least in part, via inhibition of FOXO‐mediated transcription of genes regulating muscle CHO utilisation and protein breakdown (Mallinson et al . ). Additionally, meta‐data analyses associated intensive statin therapy (up to 40 mg day −1 ) with increased risk of new‐onset diabetes compared to moderate dose therapy (Preiss et al .…”

Long-term safety of dichloroacetate in congenital lactic acidosis

“…However, impairment of pyruvate oxidation may lead to a chronic metabolic acidosis that may exacerbate bone demineralization, growth retardation, abnormal glucose tolerance, renal impairment and muscle wasting and contribute to a general pro-oxidant state associated with depletion of anti-oxidant defense mechanisms (3, 4). Given the broad spectrum of pathology associated with acute or chronic lactic acidosis, it is noteworthy that DCA stimulates residual PDC activity and decreases the adverse local tissue and/or systemic effects of lactic acidosis on cardiac or skeletal muscle function associated with exercise, insulin resistance, sepsis, ischemia, high fat feeding, or statin-induced myopathy and may inhibit tissue protein wasting (reviewed in 2, 19, 26). Together, these observations lend particular import to both circulating lactate as a clinically useful and readily obtainable biomarker of disease progression and to the potential utility of DCA in treating PDC deficiency.…”

Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate

“…We were therefore interested to investigate whether administration of DCA could correct the impairment of CHO oxidation induced by simvastatin in a rodent model [57]. Compared with control, simvastatin (80 mg/kg/body weight) increased PDK4 protein expression and reduced muscle PDCa.…”