Journal article
AMP-Activated Protein Kinase Deficiency Exacerbates Aging-Induced Myocardial Contractile Dysfunction
Aging cell, Vol.9(4), pp.592-606
08/2010
Handle:
https://hdl.handle.net/2376/106888
PMCID: PMC2910211
PMID: 20477759
Abstract
Aging is associated with myocardial dysfunction although the underlying mechanism is unclear. AMPK, a key cellular fuel sensor for energy metabolism, is compromised with aging. This study examined the role of AMPK deficiency in aging-associated myocardial dysfunction. Young or old minwild-type (WT) and transgenic mice with overexpression of a mutant AMPK α
2
subunit (kinase dead, KD) were used. AMPK α isoform activity, myocardial function and morphology were examined. DCF and JC-1 fluorescence probes were employed to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm), respectively. KD mice displayed significantly reduced α
2
but not α
1
AMPK isoform activity at both ages with a greater effect at old age. Aging itself decreased α
1
isoform activity. Cardiomyocyte contractile function, intracellular Ca
2+
handling and SERCA2a levels were compromised with aging, the effects of which were exacerbated by AMPK deficiency. H&E staining revealed cardiomyocyte hypertrophy with aging, which was more pronounced in KD mice. TEM micrographs displayed severe disruption of mitochondrial ultrastructure characterized by swollen, irregular shape and disrupted cristae in aged KD compared with WT mice. Aging enhanced ROS production and reduced ΔΨm, the effects of which were accentuated by AMPK deficiency. Immunoblotting data depicted unchanged Akt phosphorylation and a significant decrease in mitochondrial biogenesis cofactor PGC-1α in aged groups. AMPK deficiency but not aging decreased the phosphorylation of ACC and eNOS. Expression of membrane Glut4 and HSP90 was decreased in aged KD mice. Moreover, treatment of the AMPK activator metformin attenuated aging-induced cardiomyocyte contractile defects. Collectively, our data suggest a role for AMPK deficiency in aging-induced cardiac dysfunction possibly through disrupted mitochondrial function and ROS production.
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Details
- Title
- AMP-Activated Protein Kinase Deficiency Exacerbates Aging-Induced Myocardial Contractile Dysfunction
- Creators
- Subat Turdi - Center for Cardiovascular Research and Alternative Medicine & Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071Xiujuan Fan - Center for Cardiovascular Research and Alternative Medicine & Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071Ji Li - Center for Cardiovascular Research and Alternative Medicine & Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071Junxing Zhao - Department of Animal Sciences, University of Wyoming, Laramie, WY 82071Anna F Huff - Center for Cardiovascular Research and Alternative Medicine & Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071Min Du - Department of Animal Sciences, University of Wyoming, Laramie, WY 82071Jun Ren - Center for Cardiovascular Research and Alternative Medicine & Division of Pharmaceutical Sciences, University of Wyoming, Laramie, WY 82071
- Publication Details
- Aging cell, Vol.9(4), pp.592-606
- Academic Unit
- Animal Sciences, Department of
- Identifiers
- 99900546718101842
- Language
- English
- Resource Type
- Journal article