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The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity.
Biochim Biophys Acta. 2015 Aug; 1853(8):1841-9.BB

Abstract

Statins are drugs that lower blood cholesterol levels and reduce cardiovascular morbidity and mortality. They are generally well-tolerated, but myopathy is a potentially severe adverse reaction of these compounds. The mechanisms by which statins induce myotoxicity are not completely understood, but may be related to inhibition of the AKT signaling pathway. The current studies were performed to explore the down-stream effects of the statin-associated inhibition of AKT within the AKT signaling pathway and on myocyte biology and morphology in C2C12 myotubes and in mice in vivo. We exposed C2C12 myotubes to 10 μM or 50 μM simvastatin, atorvastatin or rosuvastatin for 24 h. Simvastatin and atorvastatin inhibited AKT phosphorylation and were cytotoxic starting at 10 μM, whereas similar effects were observed for rosuvastatin at 50 μM. Inhibition of AKT phosphorylation was associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1 and FoxO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of C2C12 myotubes. Furthermore, impaired AKT phosphorylation was associated with activation of caspases and PARP, reflecting induction of apoptosis. Similar findings were detected in skeletal muscle of mice treated orally with 5 mg/kg/day simvastatin for 3 weeks. In conclusion, this study highlights the importance of the AKT/mTOR signaling pathway in statin-induced myotoxicity and reveals potential drug targets for treatment of patients with statin-associated myopathies.

Authors+Show Affiliations

Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland.Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre of Applied Human Toxicology (SCAHT), University of Basel, Switzerland.Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre of Applied Human Toxicology (SCAHT), University of Basel, Switzerland. Electronic address: stephan.kraehenbuehl@usb.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25913013

Citation

Bonifacio, Annalisa, et al. "The AKT/mTOR Signaling Pathway Plays a Key Role in Statin-induced Myotoxicity." Biochimica Et Biophysica Acta, vol. 1853, no. 8, 2015, pp. 1841-9.
Bonifacio A, Sanvee GM, Bouitbir J, et al. The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity. Biochim Biophys Acta. 2015;1853(8):1841-9.
Bonifacio, A., Sanvee, G. M., Bouitbir, J., & Krähenbühl, S. (2015). The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity. Biochimica Et Biophysica Acta, 1853(8), 1841-9. https://doi.org/10.1016/j.bbamcr.2015.04.010
Bonifacio A, et al. The AKT/mTOR Signaling Pathway Plays a Key Role in Statin-induced Myotoxicity. Biochim Biophys Acta. 2015;1853(8):1841-9. PubMed PMID: 25913013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The AKT/mTOR signaling pathway plays a key role in statin-induced myotoxicity. AU - Bonifacio,Annalisa, AU - Sanvee,Gerda M, AU - Bouitbir,Jamal, AU - Krähenbühl,Stephan, Y1 - 2015/04/23/ PY - 2014/12/20/received PY - 2015/04/04/revised PY - 2015/04/17/accepted PY - 2015/4/28/entrez PY - 2015/4/29/pubmed PY - 2015/9/10/medline KW - AKT/mTOR signaling pathway KW - Apoptosis KW - Atorvastatin KW - Muscle atrophy KW - Rosuvastatin KW - Simvastatin SP - 1841 EP - 9 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1853 IS - 8 N2 - Statins are drugs that lower blood cholesterol levels and reduce cardiovascular morbidity and mortality. They are generally well-tolerated, but myopathy is a potentially severe adverse reaction of these compounds. The mechanisms by which statins induce myotoxicity are not completely understood, but may be related to inhibition of the AKT signaling pathway. The current studies were performed to explore the down-stream effects of the statin-associated inhibition of AKT within the AKT signaling pathway and on myocyte biology and morphology in C2C12 myotubes and in mice in vivo. We exposed C2C12 myotubes to 10 μM or 50 μM simvastatin, atorvastatin or rosuvastatin for 24 h. Simvastatin and atorvastatin inhibited AKT phosphorylation and were cytotoxic starting at 10 μM, whereas similar effects were observed for rosuvastatin at 50 μM. Inhibition of AKT phosphorylation was associated with impaired phosphorylation of S6 kinase, ribosomal protein S6, 4E-binding protein 1 and FoxO3a, resulting in reduced protein synthesis, accelerated myofibrillar degradation and atrophy of C2C12 myotubes. Furthermore, impaired AKT phosphorylation was associated with activation of caspases and PARP, reflecting induction of apoptosis. Similar findings were detected in skeletal muscle of mice treated orally with 5 mg/kg/day simvastatin for 3 weeks. In conclusion, this study highlights the importance of the AKT/mTOR signaling pathway in statin-induced myotoxicity and reveals potential drug targets for treatment of patients with statin-associated myopathies. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/25913013/The_AKT/mTOR_signaling_pathway_plays_a_key_role_in_statin_induced_myotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0167-4889(15)00129-9 DB - PRIME DP - Unbound Medicine ER -