Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Schirris, Tom J.J.; Renkema, G. Herma; Ritschel, Tina; Voermans, Nicol C.; Bilos, Albert; Engelen, B.G.M. van; Brandt, Ulrich; Koopman, Werner J.H.; Beyrath, Julien; Rodenburg, Richard J.; Willems, Peter H.G.M.; Smeitink, Jan A.M.; Rüssel, Frans G. M.

doi:10.1016/j.cmet.2015.08.002

Cited by 196 publications

(196 citation statements)

References 42 publications

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“…32 The mechanisms of statin myopathy are complex, also involving mitochondrial RC complex III deficiency by direct binding of the drug to the enzyme. 33 S-FGF21 did not respond to statininduced muscle events, even in the acute phase. Furthermore, despite low amounts of mtDNA deletions in skeletal muscle of normal aging individuals, 34 S-FGF21 was not increased even in people in their 10th decade.…”

Section: Discontinuation Of Statin Treatment and Clinical Remission Omentioning

confidence: 81%

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Lehtonen¹,

Forsström²,

Bottani³

et al. 2016

Neurology

176

165

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Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods:We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different musclemanifesting mitochondrial dysfunctions.Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p , 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p , 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p , 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions.Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. Classification of evidence:This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies. Neurology ® 2016;87:2290-2299 GLOSSARY ALS 5 amyotrophic lateral sclerosis; CI 5 confidence interval; CK 5 creatine kinase; FGF21 5 fibroblast growth factor 21; GDF15 5 growth and differentiation factor 15; mCRC 5 metastasized colorectal cancer; MM 5 mitochondrial myopathy; mtDNA 5 mitochondrial DNA; PBC 5 primary biliary cirrhosis; PSC 5 primary sclerosing cholangitis; RC 5 respiratory chain; S-FGF21 5 serum FGF21; tRNA 5 transfer RNA.Mitochondrial diseases are the most common form of inherited metabolic disorders. The high variability in clinical manifestation, heterogeneity of genetic causes with .150 known disease genes, 1 and scarcity of sensitive and specific biomarkers make their diagnosis challenging. Our original multicenter analysis identified fibroblast growth factor 21 (FGF21) induction in *These authors contributed equally to this work.

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Section: Discontinuation Of Statin Treatment and Clinical Remission Omentioning

confidence: 81%

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Lehtonen¹,

Forsström²,

Bottani³

et al. 2016

Neurology

176

165

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“…Mutations in structural subunits or assembly chaperones induce mitochondrial disease in humans (Koene et al, 2012;Loeffen et al, 2000;van den Heuvel and Smeitink, 2001). Inherited complex-I deficiencies are the most common OXPHOS disorders (Bénit et al, 2009), whereas myopathy has been linked to an off-target effect of statins on complex III (Schirris et al, 2015). Moreover, empirical evidence suggests that inhibition of complex I mediates the action of the antidiabetic drug metformin and is relevant in cancer treatment (Chen et al, 2007;Schöckel et al, 2015;Vatrinet et al, 2015;Zhang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

Liemburg-Apers

Wagenaars

Smeitink

et al. 2016

Journal of Cell Science

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Mitochondria play a central role in cellular energy production, and their dysfunction can trigger a compensatory increase in glycolytic flux to sustain cellular ATP levels. Here, we studied the mechanism of this homeostatic phenomenon in C2C12 myoblasts. Acute (30 min) mitoenergetic dysfunction induced by the mitochondrial inhibitors piericidin A and antimycin A stimulated Glut1-mediated glucose uptake without altering Glut1 (also known as SLC2A1) mRNA or plasma membrane levels. The serine/threonine liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK) played a central role in this stimulation. In contrast, ataxiatelangiectasia mutated (ATM; a potential AMPK kinase) and hydroethidium (HEt)-oxidizing reactive oxygen species (ROS; increased in piericidin-A-and antimycin-A-treated cells) appeared not to be involved in the stimulation of glucose uptake. Treatment with mitochondrial inhibitors increased NAD + and NADH levels (associated with a lower NAD + :NADH ratio) but did not affect the level of Glut1 acetylation. Stimulation of glucose uptake was greatly reduced by chemical inhibition of Sirt2 or mTOR-RAPTOR. We propose that mitochondrial dysfunction triggers LKB1-mediated AMPK activation, which stimulates Sirt2 phosphorylation, leading to activation of mTOR-RAPTOR and Glut1-mediated glucose uptake.

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“…The biological basis for statin-induced myopathy is not well understood, yet in vitro and in vivo studies suggest that several factors may contribute, including apoptosis [7, 8, 9, 10], reduced isoprenoid and ubiquinone (coenzyme Q 10 , CoQ 10 ) synthesis [11, 9, 12, 13, 14], and/or increased mitochondrial dysfunction [15, 16, 8, 12, 13, 17, 18]. In vitro and in vivo studies demonstrate that simvastatin can inhibit complex I [8, 17] and complex III [13] of the mitochondrial electron transport chain, which not only interferes with energy production, but also results in the generation of reactive oxygen species (ROS) that result in cellular damage.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy

et al. 2016

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HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training.

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Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Cited by 196 publications

References 42 publications

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy

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