Statin-Induced Muscle Necrosis in the Rat: Distribution, Development, and Fibre Selectivity

Abstract

Simvastatin and cerivastatin have been used to investigate the development of statin-induced muscle necrosis in the rat. This was similar for both statins and was treatment-duration dependent, only occurring after 10 days had elapsed even if the dose was increased, and still occurring after this time when dosing was terminated earlier as a result of morbidity. It was then widespread and affected all areas of the muscular system. However, even when myotoxicity was severe, particular individual muscles and some types of fibres within affected muscles were spared consistently. Fibre typing of spared muscles and of acutely necrotic fibres within affected muscles indicated a differential fibre sensitivity to statin-induced muscle necrosis. The fibres showed a necrotic response to statin administration that matched their oxidative/glycolytic metabolic nature: Least sensitive → I ↔ IIA ↔ IID ↔ IIB ← most sensitive. Type I and IIB fibres represent metabolic extremes of a continuum of metabolic properties through the fibre types with type I fibres most oxidative in metabolism and type IIB fibres most glycolytic. In addition, in some (nonnecrotic) glycolytic fibres from muscles showing early multifocal single fibre necrosis the only subcellular alterations present in isolation of any other changes were mitochondrial. These changes were characterised by an increased incidence of vacuolation and the formation of myelinoid vesicular bodies that accumulated in the subsarcolemmal areas. These findings suggest an important early involvement of mitochondria in selective glycolytic muscle fibre necrosis following inhibition of the enzyme HMG-CoA reductase.

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel

“…The mechanisms responsible for these associations are poorly understood. In an animal model of statin-induced myopathy, administration of simvastatin impaired phosphatidylinositol 3-kinase (PI3k)/Akt signaling in muscle, inducing ubiquitin and lysosomal proteolysis through up-regulation of the FOXO downstream target genes of muscle atrophy such as cathepsin-L mRNA, muscle RING finger-1 (MuRF-1), and F-box (MAFbx), and dephosphorylation of the forkhead box protein O (FOXO) (1 and 3) transcription factors [80]. In skeletal muscle tissue statin therapy can cause mitochondrial dysfunction limited typically to complex I of the respiratory chain, which increases mitochondrial NADH and the intracellular redox potential (NADH/NAD + ratio), activates pyruvate dehydrogenase kinase (PDK), and inhibits flux via the pyruvate dehydrogenase complex (PDC) [81,82].…”

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

“…They were counted in the 40 high power fields. Degenerated fibers were graded subjectively; mild-up to approximately 20% of fibers affected; moderate-up to 50% of fibers affected and severemore than 50% of fibers affected [11].…”

Bone scintigraphy of severe hypercalcemia following simvastatin induced rhabdomyolysis

“…Type 1 muscle fibers are predominantly oxidative in nature where as Type 2 fibers are glycolytic in nature. Early involvement of mitochondria in selective glycolytic muscle fiber necrosis following inhibition of the enzyme HMGCoA reductase has been shown in rats (15). Pathogenesis of delayed hypercalcemia in our patient could be due to calcium mobilization from the muscles and interstitium along with immobilization due to weakness.…”