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

• Published in: Apoptosis (London) 2008-06, Vol.13 (6), p.822-832
• Main Authors: Braga, Melissa, Sinha Hikim, Amiya P, Datta, Sanjit, Ferrini, Monica G, Brown, Danielle, Kovacheva, Ekaterina L, Gonzalez-Cadavid, Nestor F, Sinha-Hikim, Indrani
• Format: Article
• Language: English
• Subjects: Aging; Aging - physiology; Aldehydes - metabolism; Animals; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspase 2 - physiology; Caspase 9 - metabolism; Cell Biology; Glucosephosphate Dehydrogenase - metabolism; Inactivation; JNK Mitogen-Activated Protein Kinases - metabolism; Lymphoma; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Oncology; Original Paper; Oxidative stress; Oxidative Stress - physiology; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - metabolism; Regression analysis; Signal Transduction - physiology; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-008-0216-7

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.