PMID- 22723631
OWN - NLM
STAT- MEDLINE
DCOM- 20130109
LR  - 20130926
IS  - 1522-1601 (Electronic)
IS  - 0161-7567 (Linking)
VI  - 113
IP  - 4
DP  - 2012 Aug 15
TI  - Reduced hexokinase II impairs muscle function 2 wk after ischemia-reperfusion 
      through increased cell necrosis and fibrosis.
PG  - 608-18
LID - 10.1152/japplphysiol.01494.2011 [doi]
AB  - We previously demonstrated that hexokinase (HK) II plays a key role in the 
      pathophysiology of ischemia-reperfusion (I/R) injury of the heart (Smeele et al. 
      Circ Res 108: 1165-1169, 2011; Wu et al. Circ Res 108: 60-69, 2011). However, it 
      is unknown whether HKII also plays a key role in I/R injury and healing 
      thereafter in skeletal muscle, and if so, through which mechanisms. We used male 
      wild-type (WT) and heterozygous HKII knockout mice (HKII(+/-)) and performed in 
      vivo unilateral skeletal muscle I/R, executed by 90 min hindlimb occlusion using 
      orthodontic rubber bands followed by 1 h, 1 day, or 14 days reperfusion. The 
      contralateral (CON) limb was used as internal control. No difference was observed 
      in muscle glycogen turnover between genotypes at 1 h reperfusion. At 1 day 
      reperfusion, the model resulted in 36% initial cell necrosis in WT gastrocnemius 
      medialis (GM) muscle that was doubled (76% cell necrosis) in the HKII(+/-) mice. 
      I/R-induced apoptosis (29%) was similar between genotypes. HKII reduction 
      eliminated I/R-induced mitochondrial Bax translocation and oxidative stress at 1 
      day reperfusion. At 14 days recovery, the tetanic force deficit of the reperfused 
      GM (relative to control GM) was 35% for WT, which was doubled (70%) in HKII(+/-) 
      mice, mirroring the initial damage observed for these muscles. I/R increased 
      muscle fatigue resistance equally in GM of both genotypes. The number of 
      regenerating fibers in WT muscle (17%) was also approximately doubled in 
      HKII(+/-) I/R muscle (44%), thus again mirroring the increased cell death in 
      HKII(+/-) mice at day 1 and suggesting that HKII does not significantly affect 
      muscle regeneration capacity. Reduced HKII was also associated with doubling of 
      I/R-induced fibrosis. In conclusion, reduced muscle HKII protein content results 
      in impaired muscle functionality during recovery from I/R. The impaired recovery 
      seems to be mainly a result of a greater susceptibility of HKII(+/-) mice to the 
      initial I/R-induced necrosis (not apoptosis), and not a HKII-related deficiency 
      in muscle regeneration.
FAU - Smeele, Kirsten M
AU  - Smeele KM
AD  - Laboratory of Experimental Intensive Care and Anesthesiology, Department of 
      Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands.
FAU - Eerbeek, Otto
AU  - Eerbeek O
FAU - Schaart, Gert
AU  - Schaart G
FAU - Koeman, Anneke
AU  - Koeman A
FAU - Bezemer, Rick
AU  - Bezemer R
FAU - Nelson, Jessica K
AU  - Nelson JK
FAU - Ince, Can
AU  - Ince C
FAU - Nederlof, Rianne
AU  - Nederlof R
FAU - Boek, Maxim
AU  - Boek M
FAU - Laakso, Markku
AU  - Laakso M
FAU - de Haan, Arnold
AU  - de Haan A
FAU - Drost, Maarten R
AU  - Drost MR
FAU - Hollmann, Markus W
AU  - Hollmann MW
FAU - Zuurbier, Coert J
AU  - Zuurbier CJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120621
PL  - United States
TA  - J Appl Physiol (1985)
JT  - Journal of applied physiology (Bethesda, Md. : 1985)
JID - 8502536
RN  - 0 (Bax protein, mouse)
RN  - 0 (bcl-2-Associated X Protein)
RN  - 9005-79-2 (Glycogen)
RN  - EC 2.7.1.1 (Hexokinase)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Fibrosis
MH  - Glycogen/metabolism
MH  - Hexokinase/*deficiency/genetics
MH  - Hindlimb
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microcirculation
MH  - Mitochondria, Muscle/metabolism/pathology
MH  - Muscle Fatigue
MH  - *Muscle Strength
MH  - Muscle, Skeletal/*blood supply/*enzymology/pathology/physiopathology
MH  - Necrosis
MH  - Neovascularization, Physiologic
MH  - Oxidative Stress
MH  - Recovery of Function
MH  - Regeneration
MH  - Regional Blood Flow
MH  - Reperfusion Injury/*enzymology/genetics/pathology/physiopathology
MH  - Time Factors
MH  - bcl-2-Associated X Protein/metabolism
EDAT- 2012/06/23 06:00
MHDA- 2013/01/10 06:00
CRDT- 2012/06/23 06:00
PHST- 2012/06/23 06:00 [entrez]
PHST- 2012/06/23 06:00 [pubmed]
PHST- 2013/01/10 06:00 [medline]
AID - japplphysiol.01494.2011 [pii]
AID - 10.1152/japplphysiol.01494.2011 [doi]
PST - ppublish
SO  - J Appl Physiol (1985). 2012 Aug 15;113(4):608-18. doi: 
      10.1152/japplphysiol.01494.2011. Epub 2012 Jun 21.