PMID- 17786558
OWN - NLM
STAT- MEDLINE
DCOM- 20071221
LR  - 20131121
IS  - 1360-8185 (Print)
IS  - 1360-8185 (Linking)
VI  - 12
IP  - 11
DP  - 2007 Nov
TI  - Involvement of c-Jun NH2-terminal kinase and nitric oxide-mediated 
      mitochondria-dependent intrinsic pathway signaling in cardiotoxin-induced muscle 
      cell death: role of testosterone.
PG  - 1965-78
AB  - To test the hypothesis that c-Jun NH2-terminal kinase (JNK) and nitric oxide 
      (NO)-mediated signaling plays an important role in muscle cell apoptosis, we 
      examined the contribution of these molecules in muscle cell apoptosis during 
      cardiotoxin (ctx)-induced muscle injury in mice. Compared to controls, where no 
      apoptosis was detected, the percent of muscle cell apoptosis rose significantly 
      (P < 0.05) at 4 h (27%) after ctx-treatment and increased further progressively 
      up to 16 h posttreatment (80%), before it fell again at 24 h posttreatment (38%). 
      Initiation of apoptosis was preceded by JNK activation and elevated levels of 
      B-cell lymphoma-2 (BCL-2) in the mitochondrial fractions (BAX levels remained 
      unaffected). Ctx treatment also resulted in the inactivation of BCL-2 through 
      phosphorylation at serine 70, thereby perturbing the BAX/BCL-2 rheostat, and the 
      subsequent activation of the cytochrome c-mediated death pathway. Concomitant 
      administration of SP600125, a selective JNK inhibitor, or aminoguanidine (AG), a 
      selected inducible nitric oxide synthase (iNOS) inhibitor, effectively diminished 
      BCL-2 phosphorylation, suppressed cytochrome c release from mitochondria and 
      caspase activation, and significantly prevented ctx-induced muscle cell 
      apoptosis. In additional studies, we examined the role of testosterone in 
      preventing such ctx-induced muscle cell apoptosis. Collectively, the present 
      study emphasizes the role of a new signal transduction pathway involving JNK and 
      iNOS that promotes ctx-induced myocyte apoptosis by provoking BCL-2 
      phosphorylation, leading to its inactivation, and subsequent activation of the 
      intrinsic pathway signaling. Testosterone therapy has no protective effect in 
      acute muscle injury associated with increased muscle cell death after 
      ctx-treatment.
FAU - Sinha-Hikim, Indrani
AU  - Sinha-Hikim I
AD  - Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew 
      University, Los Angeles, CA 90059, USA. insinhah@cdrewu.edu
FAU - Braga, Mellisa
AU  - Braga M
FAU - Shen, Ruoqing
AU  - Shen R
FAU - Sinha Hikim, Amiya P
AU  - Sinha Hikim AP
LA  - eng
GR  - 5 S06-GM068510/GM/NIGMS NIH HHS/United States
GR  - RR-011145/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Cardiotoxins)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3XMK78S47O (Testosterone)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Cardiotoxins/*pharmacology
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/*physiology
MH  - Muscle Fibers, Skeletal/cytology/*drug effects/*enzymology
MH  - Nitric Oxide/*physiology
MH  - Signal Transduction/*physiology
MH  - Testosterone/*physiology
EDAT- 2007/09/06 09:00
MHDA- 2007/12/22 09:00
CRDT- 2007/09/06 09:00
PHST- 2007/09/06 09:00 [pubmed]
PHST- 2007/12/22 09:00 [medline]
PHST- 2007/09/06 09:00 [entrez]
AID - 10.1007/s10495-007-0120-6 [doi]
PST - ppublish
SO  - Apoptosis. 2007 Nov;12(11):1965-78. doi: 10.1007/s10495-007-0120-6.