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Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice

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Abstract

Apoptosis has been implicated as a mechanism of loss of muscle cells in normal aging and plays an important role in age-related sarcopenia. To test the hypothesis that caspase 2 and c-Jun NH2-terminal kinase (JNK)-mediated intrinsic pathway signaling contribute to skeletal muscle cell apoptosis in aging, we compared activation of caspase 2 and JNK and the in vivo expression of 4-hydroxynonenal protein adducts (4-HNE), inducible nitric oxide synthase (iNOS), glucose-6-phosphate dehydrogenase (G6PDH), B-cell lymphoma-2 (BCL-2), BAX, and phospho-BCL-2 in gastrocnemius muscles of young (5 months old) and old (25 months old) mice. A distinct age-related increase in 4-HNE and iNOS expression was readily detected in mice. Increased oxidative stress and iNOS induction were further accompanied by a decrease in G6PDH expression, activation of caspase 2 and JNK, and inactivation of BCL-2 through phosphorylation at serine 70, and caspase 9 activation. Regression analysis further revealed that increased muscle cell death in aging was significantly correlated with changes in the levels of these molecules. Taken together, our data indicate that caspase 2 and JNK-mediated intrinsic pathway signaling is one of the mechanisms involved in age-related increase in muscle cell apoptosis.

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Acknowledgments

This work was supported by a grant from the American Federation of Aging Research (to I.S-H). Additional support was provided by MBRS grant 5 SO6-GM068510 (to I.S-H) and RCMI Clinical Research Infrastructure Initiative grant RR-011145 (to K. Norris) from the National Institutes of Health.

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Authors and Affiliations

  1. Division of Endocrinology, Metabolism, and Molecular Medicine (I.S.-H;M.B; R.S), Charles R. Drew University, Los Angeles, CA, 90059, USA

    Melissa Braga, Monica G. Ferrini, Danielle Brown, Ekaterina L. Kovacheva, Nestor F. Gonzalez-Cadavid & Indrani Sinha-Hikim

  2. Division of Endocrinology, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA and Los Angeles Biomedical Research Institute, Torrance, CA, 90509, USA

    Amiya P. Sinha Hikim, Sanjit Datta & Nestor F. Gonzalez-Cadavid

  3. Los Angeles Biomedical Research Institute, Torrance, CA, 90509, USA

    Sanjit Datta & Nestor F. Gonzalez-Cadavid

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  1. Melissa Braga
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  2. Amiya P. Sinha Hikim
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  3. Sanjit Datta
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  4. Monica G. Ferrini
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  7. Nestor F. Gonzalez-Cadavid
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  8. Indrani Sinha-Hikim
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Correspondence to Indrani Sinha-Hikim.

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Braga, M., Sinha Hikim, A.P., Datta, S. et al. Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice. Apoptosis 13, 822–832 (2008). https://doi.org/10.1007/s10495-008-0216-7

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