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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Authors: | Melissa Braga Amiya P. Sinha Hikim Sanjit Datta Monica G. Ferrini Danielle Brown Ekaterina L. Kovacheva Nestor F. Gonzalez-Cadavid Indrani Sinha-Hikim |
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Affiliation: | (1) Division of Endocrinology, Metabolism, and Molecular Medicine (I.S.-H;M.B; R.S), Charles R. Drew University, Los Angeles, CA 90059, USA;(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;(3) Los Angeles Biomedical Research Institute, Torrance, CA 90509, USA |
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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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Keywords: | Oxidative stress Caspase 2 JNK BCL-2 phosphorylation Muscle cell apoptosis Aging Mice |
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