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... The results of this study suggest the use of DCA could offer potential to prevent statin myopathy in the clinic, particularly as the highest dose administered (40 mg kg −1 day −1 ) is less than that previously administered to humans. DCA has been used clinically for the treatment of several conditions, including lactic acidosis (100 mg kg −1 day −1 ; Stacpoole et al. 1988), diabetes mellitus (50 mg kg −1 day −1 ; Stacpoole et al. 1978), hyperlipoproteinaemia (50 mg kg −1 day −1 ; Stacpoole et al. 1978), mitochondrial encephalomyopathies (2.4 g day −1 ; Curto et al. 2006) and to offset muscle fatigue associated with anaerobic ATP production during ischaemic muscle contraction (50 mg kg −1 ; Timmons et al. 1996Timmons et al. , 1998aTimmons et al. , 1998b. Chronic use (months to a year) of DCA is, however, associated with adverse side-effects, which has detracted from its widespread use (Kurlemann et al. 1995;Stacpoole et al. 1998;Spruijt et al. 2001). ...
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.
Emerging evidence indicates there is a complex interplay between metabolism and chronic disorders in the nervous system. In particular, the pyruvate dehydrogenase (PDH) kinase (PDK)–lactic acid axis is a critical link that connects metabolic reprogramming and the pathophysiology of neurological disorders. PDKs, via regulation of PDH complex activity, orchestrate the conversion of pyruvate either aerobically to acetyl-CoA, or anaerobically to lactate. The kinases are also involved in neurometabolic dysregulation under pathological conditions. Lactate, an energy substrate for neurons, is also a recently acknowledged signaling molecule involved in neuronal plasticity, neuron–glia interactions, neuroimmune communication, and nociception. More recently, the PDK–lactic acid axis has been recognized to modulate neuronal and glial phenotypes and activities, contributing to the pathophysiologies of diverse neurological disorders. This review covers the recent advances that implicate the PDK–lactic acid axis as a novel linker of metabolism and diverse neuropathophysiologies. We finally explore the possibilities of employing the PDK–lactic acid axis and its downstream mediators as putative future therapeutic strategies aimed at prevention or treatment of neurological disorders.
