Ageing-induced decline in physical endurance in mice is associated with decrease in cardiac SUR2A and increase in cardiac susceptibility to metabolic stress: therapeutic prospects for up-regulation of SUR2A.
Ageing is characterized by decline in physical endurance which has been suggested to be partly due to diminished functional and adaptive reserve capacity of the heart. Ageing is associated with decrease in numbers of sarcolemmal ATP-sensitive K(+) (K(ATP)) channels, but whether this has anything to do with ageing-induced decline in physical endurance is yet to be determined. We have previously shown that the numbers of sarcolemmal K(ATP) channels are controlled by the level of expression of SUR2A, a K(ATP) channel regulatory subunit. Here, we have found that ageing decreases the level of SUR2A mRNA in the heart without affecting expression of pore-forming K(ATP) channel subunits, Kir6.1 and Kir6.2. This effect of ageing was associated with decrease in levels of fully-assembled sarcolemmal K(ATP) channels. At the same time, ageing was associated with decreased physical endurance. In order to determine whether increased expression of SUR2A would counteract ageing-induced decrease in physical endurance, we have taken advantage of mice which SUR2A levels are regulated by more efficient CMV promoter. These mice had increased resistance of cardiomyocytes to metabolic stress/hypoxia and increased physical endurance when compared to the wild type. In transgenic mice, ageing did not affect the level of SUR2A mRNA in the heart and the level of fully-assembled sarcolemmal K(ATP) channels. The effect of increased SUR2A to resistance of cardiomyocytes to hypoxia and physical endurance was retained in old mice. The magnitude of these effects was such that they were significantly increased even when compared to those in wild type young mice. We conclude that (1) the level of SUR2A expression in the heart is important factor in regulating physical endurance, (2) ageing-induced decrease in cardiac SUR2A is, at least in part, responsible for ageing-induced decline in physical fitness and (3) up-regulation of SUR2A could be a viable strategy to counteract ageing-induced decline in physical endurance.
Division of Medical Sciences/MACHS, Centre for Cardiovascular and Lung Biology, Ninewells Hospital & Medical School, University of Dundee, Scotland, UK.
Rajni
R
Sudhir
Andriy
A
Sukhodub
Qingyou
Q
Du
Sofija
S
Jovanović
Aleksandar
A
Jovanović
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010807:Physical Endurance / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D064233:Sulfonylurea Receptors; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; C577511:Abcc9 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors