Involvement of oxidative stress and caspase 2-mediated intrinsic pathway signaling in age-related increase in muscle cell apoptosis in mice.
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 NH(2)-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.
Braga
Melissa
M
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University, Los Angeles, CA 90059, USA.
Sinha Hikim
Amiya P
AP
Datta
Sanjit
S
Ferrini
Monica G
MG
Brown
Danielle
D
Kovacheva
Ekaterina L
EL
Gonzalez-Cadavid
Nestor F
NF
Sinha-Hikim
Indrani
I
D000375:Aging / Q000502:physiology*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053143:Caspase 2 / Q000502:physiology*; D053453:Caspase 9 / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000447:Aldehydes; D019253:Proto-Oncogene Proteins c-bcl-2; D005954:Glucosephosphate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D053143:Caspase 2; D053453:Caspase 9; C027576:4-hydroxy-2-nonenal