Drastic reduction in the luminal Ca2+-binding proteins calsequestrin and sarcalumenin in dystrophin-deficient cardiac muscle

Luminal Ca2+ -binding proteins play a central role in mediating between Ca2+ -uptake and Ca2+ -release during the excitation-contraction-relaxation cycle in muscle fibres. In the most commonly inherited neuromuscular disorder, Duchenne muscular dystrophy (DMD), the reduced expression of key Ca2+ -binding proteins causes abnormal Ca2+ -buffering in the sarcoplasmic reticulum (SR) of skeletal muscle. The heart is also affected in dystrophinopathies, as manifested by the pathological replacement of cardiac fibres by connective and fatty tissue. We therefore investigated whether similar changes occur in the abundance of luminal Ca2+ -regulatory elements in dystrophin-deficient cardiac fibres. Two-dimensional immunoblotting of total cardiac extracts was employed to unequivocally determine potential changes in the expression levels of SR components. Interestingly, the expression of the histidine-rich Ca2+ -binding protein was increased in the dystrophic heart. In contrast, the major Ca2+ -reservoir protein of the terminal cisternae, calsequestrin (CSQ), and the Ca2+ -shuttle and ion-binding protein of the longitudinal tubules, sarcalumenin, were drastically reduced in cardiac mdx fibres. This result agrees with the recently reported decrease in the Ca2+ -release channel and Ca2+ -ATPase in the mdx heart. Abnormal Ca2+ -handling appears to play a major role in the molecular pathogenesis of the cardiac involvement in X-linked muscular dystrophy