Abstract
Statin therapy may induce skeletal muscle damage ranging from myalgia to severe rhabdomyolysis. Our previous preclinical studies showed that statin treatment in rats involves the reduction of skeletal muscle ClC-1 chloride channel expression and related chloride conductance (gCl). An increase of the activity of protein kinase C theta (PKC theta) isoform, able to inactivate ClC-1, may contribute to destabilize sarcolemma excitability. These effects can be detrimental for muscle function leading to drug-induced myopathy. Our goal is to study the causes of statin-induced muscle side effects in patients at the aim to identify biological markers useful to prevent and counteract statin-induced muscle damage. We examined 10 patients, who experienced myalgia and hyper-CK-emia after starting statin therapy compared to 9 non-myopathic subjects not using lipid-lowering drugs. Western Blot (WB) analysis showed a 40% reduction of ClC-1 protein and increased expression of phosphorylated PKC in muscle biopsies of statin-treated patients with respect to untreated subjects, independently from their age and statin type. Real-time PCR analysis showed that despite reduction of the protein, the ClC-1 mRNA was not significantly changed, suggesting post-transcriptional modification. The mRNA expression of a series of genes was also evaluated. MuRF-1 was increased in accord with muscle atrophy, MEF-2, calcineurin (CN) and GLUT-4 transporter were reduced, suggesting altered transcription, alteration of glucose homeostasis and energy deficit. Accordingly, the phosphorylated form of AMPK, measured by WB, was increased, suggesting cytoprotective process activation. In parallel, mRNA expression of Notch-1, involved in muscle cell proliferation, was highly expressed in statin-treated patients, indicating active regeneration. Also, PGC-1-alpha and isocitrate-dehydrogenase increased expression together with increased activity of mitochondrial citrate-synthase, measured by spectrophotometric assay, suggests mitochondrial biogenesis. Thus, the reduction of ClC-1 protein and consequent sarcolemma hyperexcitability together with energy deficiency appear to be among the most important alterations to be associated with statin-related risk of myopathy in humans. Thus, it may be important to avoid statin treatment in pathologies characterized by energy deficit and chloride channel malfunction. This study validates the measure of ClC-1 expression as a reliable clinical test for assessing statin-dependent risk of myopathy.
Highlights
Statin therapy is important for the prevention and treatment of cardiovascular diseases (CVD), which represent the primary cause of mortality worldwide
We found that the mRNA amount of ClC-1 channel was similar between the two groups, the expression of the ClC-1 protein was significantly decreased by 41.0 ± 1.8% in muscle biopsies of patients in therapy with statin (Figure 3)
We observed a significant increase of PKCθ mRNA in muscle biopsies of statin-treated myopathic patients with respect to the untreated subjects (Figure 3)
Summary
Statin therapy is important for the prevention and treatment of cardiovascular diseases (CVD), which represent the primary cause of mortality worldwide. Many large scale multi-center trials have demonstrated the efficacy of these compounds in reducing cardiovascular event rates and in improving survival (Vaughan and Gotto, 2004) For this reason, statins are by far the most common first-line drugs because of their predictable clinical benefits in reducing low-density lipoprotein cholesterol. Statins have been proposed in therapy as antiinflammatory and anti-cancer These drugs can produce a variety of skeletal muscle adverse reactions ranging from muscle pain to muscle cell damage and eventually leading to severe rhabdomyolysis (Vaughan and Gotto, 2004). Such effects can reduce compliance or require statins discontinuation, exposing the patients to life-threatening cardiovascular event. Additional parameters could be affected because calcium signaling and energetic pathway are changed in skeletal muscle of statin-treated rats (Liantonio et al, 2007; Camerino et al, 2011)
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