Altered mechanisms of Ca2+ transport may underlie the contractile dysfunctions that have been frequently reported to occur in diabetic cardiac and skeletal muscle tissues. Calsequestrin, a high-capacity Ca2+-binding protein, is involved in the regulation of the excitation-contraction-relaxation cycle of both skeletal and cardiac muscle fibres. We have investigated the expression of calsequestrin and Ca2+ binding in cardiac and skeletal muscle from streptozotocin-induced diabetic rat. Immunoblotting of microsomal membranes from normal and streptozotocin-induced diabetic muscle revealed no significant changes in heart, but an increase in the relative abundance of calsequestrin and calsequestrin-like proteins in skeletal muscle. In analogy, the overall Ca2+-binding capacity of sarcoplasmic reticulum vesicles from diabetic skeletal muscle was drastically increased. The expression of fast muscle marker proteins was not affected, indicating that no relevant fibre transformation occurred in streptozotocin-treated rat muscles. The up-regulation of the high-capacity Ca2+-binding element calsequestrin might represent a compensatory mechanism of diabetic skeletal muscle. An increased Ca2+-buffering capacity of the sarcoplasmic reticulum lumen might counteract elevated cytosolic Ca2+ levels in diabetes thereby preventing Ca2+-dependent myo-necrosis.