Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage.
Aging is associated with hepatic growth hormone resistance resulting in a fall in serum insulin-like growth factor 1 (IGF-1) level. However, whether loss of IGF-1 contributes to cardiac aging is unclear. This study was designed to examine the effect of cardiac overexpression of IGF-1 on cardiomyocyte contractile function in young (3 mo) and old (26-28 mo) mice. Cardiomyocyte contractile function was evaluated, including peak shortening (PS), time to 90% PS, time to 90% relengthening (TR(90)), and maximal velocity of shortening/relengthening (+/-dL/dt). Levels of advanced glycation end product, protein carbonyl, sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban, and Na(+)/Ca(2+) exchanger were assessed by Western blot analysis. SERCA activity was measured by (45)Ca(2+) uptake. Aging induced a decline in plasma IGF-1 levels. Aged cells exhibited depressed +/-dL/dt, prolonged TR(90), and a steeper PS decline in response to increasing stimulus frequency compared with those in young myocytes. IGF-1 transgene alleviated aging-induced loss in plasma IGF-1 and aging-induced mechanical defects with little effect in young mice. The beneficial effect of IGF-1 transgene on aging-associated cardiomyocyte contractile dysfunction was somewhat mimicked by short-term in vitro treatment of recombinant IGF-1 (500 nM). Advanced glycation end product and protein carbonyl levels were higher in aged mice, which were not affected by IGF-1. Expression of SERCA2a (but not Na(+)/Ca(2+) exchanger and phospholamban) and SERCA activity were reduced with aging, which was ablated by the IGF-1 transgene. Collectively, our data suggest a beneficial role of IGF-1 in aging-induced cardiac contractile dysfunction, possibly related to improved Ca(2+) uptake.
Li
Qun
Q
Div of Pharmaceutical Science & Center for Cardiovascular Research and Alternative Medicine, Univ of Wyoming, Laramie, WY 82071-3375, USA.
Wu
Shan
S
Li
Shi-Yan
SY
Lopez
Faye L
FL
Du
Min
M
Kajstura
Jan
J
Anversa
Piero
P
Ren
Jun
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003971:Diastole / Q000502:physiology*; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006331:Heart Diseases / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D032342:Muscle Cells / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D016276:Ventricular Function
D007334:Insulin-Like Growth Factor I; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium