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Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage

¹Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine and ²Department of Animal Sciences, Laramie, Wyoming; and ³Department of Medicine, New York Medical College, Valhalla, New York

Submitted 21 September 2006 ; accepted in final form 31 October 2006

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 (TR₉₀), and maximal velocity of shortening/relengthening (±dL/dt). Levels of advanced glycation end product, protein carbonyl, sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA2a), phospholamban, and Na⁺/Ca²⁺ exchanger were assessed by Western blot analysis. SERCA activity was measured by ⁴⁵Ca²⁺ uptake. Aging induced a decline in plasma IGF-1 levels. Aged cells exhibited depressed ±dL/dt, prolonged TR₉₀, 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⁺/Ca²⁺ 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 Ca²⁺ uptake.

cardiomyocytes; contractile function; calcium regulatory protein; senescence

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