PMID- 25980021
OWN - NLM
STAT- MEDLINE
DCOM- 20150928
LR  - 20200930
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 309
IP  - 2
DP  - 2015 Jul 15
TI  - Hyperhomocysteinemia inhibits satellite cell regenerative capacity through p38 
      alpha/beta MAPK signaling.
PG  - H325-34
LID - 10.1152/ajpheart.00099.2015 [doi]
AB  - Chronic failure in maintenance and regeneration of skeletal muscles leads to 
      lower muscle mass (sarcopenia), muscle weakness, and poor response to injury. 
      Evidence suggests that aberrant p38 MAPK signaling undermines the repair process 
      after injury in aged mice. Previous studies have shown that hyperhomocysteinemia 
      (HHcy) has been associated with muscle weakness and lower than normal body 
      weights. However, whether or not HHcy condition also compromises skeletal muscle 
      regenerative capabilities is not clear. In the current study, we show that CBS-/+ 
      mice, a model for HHcy condition, exhibited compromised regenerative function and 
      cell proliferation upon injury. However, there was no significant difference in 
      Pax7 expression levels in the satellite cells from CBS-/+ mouse skeletal muscles. 
      Interestingly, the satellite cells from CBS-/+ mice not only exhibited diminished 
      in vitro proliferative capabilities, but also there was heightened oxidative 
      stress. In addition, there was enhanced p38 MAPK activation as well as p16 and 
      p21 expression in the CBS-/+ mouse satellite cells. Moreover, the C2C12 myoblasts 
      also exhibited higher p38 MAPK activation and p16 expression upon treatment with 
      homocysteine in addition to enhanced ROS presence. Tissue engraftment potential 
      and regeneration after injury were restored to some extent upon treatment with 
      the p38-MAPK inhibitor, SB203580, in the CBS-/+ mice. These results together 
      suggest that HHcy-induced diminished satellite cell proliferation involves 
      excessive oxidative stress and p38 MAPK signaling. Our study further proposes 
      that HHcy is a potential risk factor for elderly frailty, and need to be 
      considered as a therapeutic target while designing the alleviation 
      interventions/postinjury rehabilitation measures for adults with HHcy.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Veeranki, Sudhakar
AU  - Veeranki S
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      Kentucky s0veer02@louisville.edu.
FAU - Lominadze, David
AU  - Lominadze D
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      Kentucky.
FAU - Tyagi, Suresh C
AU  - Tyagi SC
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      Kentucky.
LA  - eng
GR  - R01 NS084823/NS/NINDS NIH HHS/United States
GR  - R01 HL074185/HL/NHLBI NIH HHS/United States
GR  - R01 HL108621/HL/NHLBI NIH HHS/United States
GR  - NS-84823/NS/NINDS NIH HHS/United States
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - P30 GM103507/GM/NIGMS NIH HHS/United States
GR  - HL-108621/HL/NHLBI NIH HHS/United States
GR  - HL-74185/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150515
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Cystathionine beta-Synthase/deficiency/genetics
MH  - Disease Models, Animal
MH  - Enzyme Activation
MH  - Hyperhomocysteinemia/*enzymology/genetics/pathology/physiopathology
MH  - *MAP Kinase Signaling System/drug effects
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle, Skeletal/drug effects/*enzymology/pathology/physiopathology
MH  - Oxidative Stress
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - *Regeneration
MH  - Sarcopenia/enzymology/pathology/physiopathology
MH  - Satellite Cells, Skeletal Muscle/drug 
      effects/*enzymology/pathology/transplantation
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
PMC - PMC4504963
OTO - NOTNLM
OT  - CBS
OT  - hyperhomocysteinemia
OT  - p16
OT  - p21
OT  - p38 MAPK
OT  - reactive oxygen species
OT  - skeletal muscle
EDAT- 2015/05/17 06:00
MHDA- 2015/09/29 06:00
PMCR- 2016/07/15
CRDT- 2015/05/17 06:00
PHST- 2015/02/09 00:00 [received]
PHST- 2015/05/11 00:00 [accepted]
PHST- 2015/05/17 06:00 [entrez]
PHST- 2015/05/17 06:00 [pubmed]
PHST- 2015/09/29 06:00 [medline]
PHST- 2016/07/15 00:00 [pmc-release]
AID - ajpheart.00099.2015 [pii]
AID - H-00099-2015 [pii]
AID - 10.1152/ajpheart.00099.2015 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2015 Jul 15;309(2):H325-34. doi: 
      10.1152/ajpheart.00099.2015. Epub 2015 May 15.