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Inhibition of iPLA 2 β and of stretch‐activated channels by doxorubicin alters dystrophic muscle function
Author(s) -
Ismail H M,
Dorchies O M,
Perozzo R,
Strosova M K,
Scapozza L,
Ruegg U T
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12188
Subject(s) - myogenesis , myocyte , mdx mouse , duchenne muscular dystrophy , intracellular , sarcolemma , medicine , extracellular , biology , chemistry , skeletal muscle , endocrinology , microbiology and biotechnology , dystrophin
Background and Purpose Chronic elevation in intracellular Ca 2+ concentration participates in death of skeletal muscle from mdx mice, a model for D uchenne muscular dystrophy ( DMD ). Candidate pathways mediating this Ca 2+ overload involve store‐operated channels ( SOCs ) and stretch‐activated channels ( SACs ), which are modulated by the Ca 2+ ‐independent form of PL A 2 ( iPLA 2 ). We investigated the effect of doxorubicin ( D ox), a chemotherapeutic agent reported to inhibit iPLA 2 in other systems, on the activity of this enzyme and on the consequences on Ca 2+ handling and muscle function in mdx mice. Experimental Approach Effects of D ox on iPLA 2 activity, reactive oxygen species production and on Ca 2+ influx were investigated in C2C12 and mdx myotubes. The mechanism of D ox‐mediated iPLA 2 inhibition was evaluated using purified 6x histidine‐tagged enzyme. Aequorin technology was used to assess Ca 2+ concentrations underneath the plasma membrane. Isolated muscles were exposed to fatigue protocols and eccentric contractions to evaluate the effects of D ox on muscle function. Key Results D ox at 1–30 μM inhibited iPLA 2 activity in cells and in the purified enzyme. D ox also inhibited SAC ‐ but not SOC ‐mediated Ca 2+ influx in myotubes. Stimulated elevations of Ca 2+ concentrations below the plasmalemma were also blocked. Exposure of excised muscle to D ox was not deleterious to force production and promoted recovery from eccentric contractions. Conclusions and Implications D ox showed efficacy against targets known to play a role in the pathology of DMD , namely iPLA 2 and SAC . The potent SAC inhibitory effect of D ox is a novel finding that can explain partly the cardiomyopathy seen in chronic anthracycline treatment.