Experimental Chloroquine Myopathy: Morphological and Biochemical Studies

Abstract

Morphological and biochemical studies were performed on the soleus muscles of rats receiving a daily intraperitoneal injection of 50 mg chloroquine chloride (CQ) per kilogram of body weight. Light microscopy showed mild to moderate variations in fiber size, numerous dense membranous bodies and vacuoles. The vacuoles were ringed by material that was intensely basophilic in hematoxylin-eosin preparations, resembling rimmed vacuoles in the muscle fibers of distal myopathy. Segmental degradation or necrosis was often observed. The ³H-leucine uptake by myofibrillar and soluble sarcoplasmic fractions in CQ-treated muscles was the same as in the controls. The significant increases in lysosomal (cathepsin B & L, B and D) proteases and thiol protease inhibitor occurred in the earlier stages of CQ-induced myopathy, when hardly any autophagic vacuoles or dense bodies were observable by light microscopy. We conclude that the overdevelopment of autophagic vacuoles and the significant increases in lysosomal protease activity in muscle tissues may be important in the development of the focal degradation and necrosis of CQ-treated muscles.

Expression of Autophagy-Associated Genes in Skeletal Muscle: An Experimental Model of Chloroquine-Induced Myopathy

“…Previous studies have reported marked and early accumulation of rimmed vacuoles consisting of dense granular bodies and variously sized vacuoles in the denervated muscles of chloroquine-treated rats [1][2][3] . By contrast, these vacuoles were very rare in the contralateral, innervated chloroquine-treated muscles as well as in the innervated and denervated muscles of saline-treated rats.…”

“…Chloroquine, a lysosomotrophic agent, modulates autophagic protein degradation in the lysosome system, thereby inducing the formation of rimmed vacuoles consisting of dense granular bodies and vacuoles including many variably sized and shaped autophagosomes in skeletal muscles [1][2][3] . We previously demonstrated an increased number of rimmed vacuoles in denervated chloroquine-treated rat muscle but not in innervated chloroquine-treated muscle or in innervated or denervated muscles of saline-treated rats [2] .…”

Myopathy Related to Administration of a Cationic Amphiphilic Drug and the Use of Multidose Drug Distribution Analysis to Predict its Occurrence

“…TOXICOLOGIC PATHOLOGY nor the pharmacology of the compounds adequately account for the myotoxic effects of the drugs (Schmalbruch, 1980;Kumamoto et al, 1989). Cationic amphiphilic drugs may accumulate in lysosomes, inhibit activity of lysosomal enzymes, and bind to phospholipids in membranes in general (Hostetler, 1984;Reasor, 1989).…”

“…All of these effects could theoretically occur independently of the formation of LLBs. It has also been suggested that the accumulation of material within lysosomes injures lysosomal membranes and increases their permeability or makes the lysosomes fragile (Kumamoto et al, 1989). Subsequent leakage of proteolytic enzymes into the cytoplasm could damage myofibrils.…”

Epididymal and Systemic Phospholipidosis in Rats and Dogs Treated with the Dopamine D3 Selective Antagonist PNU-177864

“…Phospholipidosis is sometimes associated with tissue injury in preclinical animal species and man; however, establishing a direct relationship between phospholipid accumulation and cell injury is difficult (Fardeau et al, 1979;Schmalbruch, 1980;Kumamato et al, 1989;Reasor, 1989;Halliwell, 1997;Yano, 2002). For this reason, it is important that safety biomarkers are identified in preclinical studies for the clinical monitoring of patients.…”