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Doxorubicin stimulates catabolism in C2C12 myotubes
Author(s) -
Gilliam Laura A. A.,
Moylan Jennifer S.,
Patterson Elaine W.,
Wilson Anne S.,
Reid Michael B.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.801.4
Subject(s) - myogenesis , doxorubicin , skeletal muscle , downregulation and upregulation , chemistry , p38 mitogen activated protein kinases , mapk/erk pathway , muscle atrophy , endocrinology , medicine , kinase , chemotherapy , biochemistry , gene
Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing chemotherapy. Previous studies in mice show that the E3 ubiquitin ligase, MAFbx/atrogin‐1 is upregulated in skeletal muscle following doxorubicin administration, an effect regulated by p38 MAPK signaling. Activation of p38 MAPK also promotes caspase‐3 activation. These findings led us to hypothesize that doxorubicin causes skeletal muscle atrophy through p38 MAPK signaling, leading to the upregulation of MAFbx/atrogin‐1 and caspase‐3. We measured the loss of myofibrillar proteins in C2C12 myotubes exposed to doxorubicin (0.2 μM, 48 hrs). Compared to control, actin (mean ± SE; −49 ± 4 %, n=3, p<0.01) and myosin (−40 ± 9 %, n=11, p<0.05) proteins decreased. p38 MAPK phosphorylation was elevated in 30 mins following doxorubicin exposure (16 ± 3 %, n=6, p<0.05). Doxorubicin increased MAFbx/atrogin‐1 mRNA 16 hrs (74 ± 8%, n=3, p<0.01) and 24 hrs (132 ± 8 %, n=3, p<0.01) following exposure. Caspase‐3, both precursor and active form, were elevated 6 hrs (precursor: 25 ± 7 %, n=3, p<0.05; active: 125 ± 35 %, n=3) and 24 hrs (precursor: 36 ± 6, n=3, p<0.01; active: 87 ± 12 %, n=3, p<0.01) following doxorubicin. Our data shows that doxorubicin causes skeletal muscle protein loss, which may be mediated through p38 MAPK signaling and upregulation of MAFbx/atrogin‐1 and caspase‐3. Supported by: T32 HL086341‐02 (EWP) and AHA predoctoral fellowship(LAAG)