The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Abstract

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins.

Structural Changes in the Skeletal Muscle Fiber of Adult Male Albino Rat Following Atorvastatin Treatment; the Possible Mechanisms of Atorvastatin Induced Myotoxicity

“…The observation that statin myotoxicity affects type II, glycolytic muscle fibers more than type I, oxidative fibers [16] could be explained by decreased mitochondrial number/function in pale, glycolytic muscle enhances susceptibility to muscle damage and wasting. This observation could be also explained by the protective effect of PGC-1α gene expression which is greater in oxidative fibers [13]. Overexpression of PGC-1α gene, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented statin-induced muscle damage [38].…”

“…Eng et al, [12] reported that vastus medialis of the quadriceps femoris muscle mostly are formed of type II white fibers. Statins affect type II muscle fibers mainly [11,13]. That is the reason for doing the current study on that muscle in particular.…”

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

“…Recent experiments have shown that MAFbx/Atrogin-1 is also expressed in statin-induced muscle injury and suggests similarities between atrophy and myopathy mechanisms 73 . MAFbx/Atrogin-1 mRNA levels were significantly higher in muscle biopsies from a set of statin-treated patients with muscle fatigue symptoms than in control biopsy samples (in agematched patients undergoing knee replacement) 73 .…”

Proteolysis by the Ubiquitin-Proteasome System and Kidney Disease

“…18 Recent findings indicate that the atrogin-1/MAFbx E3 ligase also mediates the muscle injury induced by statins. 19 The mechanism stimulating expression of these E3 ligases in muscle involves both a decrease in insulin/IGF-1 signaling and an increase in glucocorticoids. 20 -22 Investigations into the complications of CKD indicate that the same factors activate Ub conjugation and ultimately, muscle protein degradation, in conditions such as inflammation, acidosis, and excess angiotensin II, 20,[23][24][25] which are partially offset by the activity of the X chromosome-linked inhibitor of apoptosis protein, XIAP.…”