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Updated: May 9, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Inhibition of iPLA2 β and of stretch-activated channels by doxorubicin alters dystrophic muscle function
H M Ismail1, O M Dorchies, R Perozzo
1Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
Background And Purpose:
Chronic elevation in intracellular Ca(2+) concentration participates in death of skeletal muscle from mdx mice, a model for Duchenne 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 A2 (iPLA2 ). We investigated the effect of doxorubicin (Dox), a chemotherapeutic agent reported to inhibit iPLA2 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 Dox on iPLA2 activity, reactive oxygen species production and on Ca(2+) influx were investigated in C2C12 and mdx myotubes. The mechanism of Dox-mediated iPLA2 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 Dox on muscle function.
Key Results:
Dox at 1-30 μM inhibited iPLA2 activity in cells and in the purified enzyme. Dox 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 Dox was not deleterious to force production and promoted recovery from eccentric contractions.
Conclusions And Implications:
Dox showed efficacy against targets known to play a role in the pathology of DMD, namely iPLA2 and SAC. The potent SAC inhibitory effect of Dox is a novel finding that can explain partly the cardiomyopathy seen in chronic anthracycline treatment.
Insights
Doxorubicin inhibits calcium-independent phospholipase A2 (iPLA2) and stretch-activated channels (SACs) in Duchenne muscular dystrophy models. This suggests a potential therapeutic role for doxorubicin in managing muscle dysfunction and cardiomyopathy.
Area of Science:
- Biochemistry
- Cell Biology
- Muscle Physiology
Background:
- Chronic intracellular Ca(2+) elevation contributes to skeletal muscle death in Duchenne muscular dystrophy (DMD).
- Store-operated channels (SOCs) and stretch-activated channels (SACs) are implicated in Ca(2+) overload, modulated by Ca(2+)-independent phospholipase A2 (iPLA2).
Purpose of the Study:
- Investigate doxorubicin's (Dox) effect on iPLA2 activity.
- Assess Dox's impact on Ca(2+) handling and muscle function in mdx mice, a DMD model.
Main Methods:
- Examined Dox effects on iPLA2 activity, reactive oxygen species, and Ca(2+) influx in C2C12 and mdx myotubes.
- Evaluated Dox-mediated iPLA2 inhibition using purified enzyme and aequorin technology for Ca(2+) measurements.
- Assessed Dox's impact on isolated muscle force production and recovery from eccentric contractions.
Main Results:
- Dox inhibited iPLA2 activity in cells and purified enzyme.
- Dox suppressed SAC-mediated, but not SOC-mediated, Ca(2+) influx and stimulated Ca(2+) elevations.
- Dox exposure did not impair muscle force production and aided recovery from eccentric contractions.
Conclusions:
- Dox effectively targets iPLA2 and SAC, key players in DMD pathology.
- Dox's potent SAC inhibition offers a novel explanation for anthracycline-induced cardiomyopathy.
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