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Department of Physiology, The University of Western Ontario, London, Ontario, Canada N6A 5C1
Diminished
Ca2+-sequestering activity of the
sarcoplasmic reticulum (SR) is implicated in the age-associated slowing
of cardiac muscle relaxation. In attempting to further define the
underlying mechanisms, the present study investigated the impact of
aging on the contents of major SR
Ca2+-cycling proteins and SR
protein phosphorylation by endogenous Ca2+/calmodulin-dependent protein
kinase (CaM kinase). The studies were performed using homogenates and
SR vesicles derived from the ventricular myocardium of adult (6-8
mo old) and aged (26-28 mo old) Fischer 344 rats. Western
immunoblotting analysis showed no significant age-related difference in
the relative amounts of ryanodine
receptor-Ca2+-release channel
(RyR-CRC), the Ca2+-storage
protein calsequestrin,
Ca2+-pumping ATPase
(Ca2+-ATPase), and
Ca2+-ATPase-regulatory protein
phospholamban (PLB) in SR or homogenate. On the other hand, the
relative amount of immunoreactive CaM kinase II (
-isoform) was
~50% lower in the aged heart. CaM kinase-mediated phosphorylation of
RyR-CRC, Ca2+-ATPase, and PLB was
reduced significantly (~25-40%) in the aged compared with adult
rat. ATP-dependent Ca2+-uptake
activity of SR and the stimulatory effect of calmodulin on
Ca2+ uptake were also reduced
significantly with aging. Treatment of SR vesicles with anti-PLB
antibody (PLBab) invoked relatively less stimulation of
Ca2+ uptake in the aged (
26%)
compared with the adult (65%) rat. Ca2+-ATPase but not PLB underwent
phosphorylation by CaM kinase in PLBab-treated SR with resultant
stimulation of Ca2+ uptake. The
rates of Ca2+ uptake by
PLBab-treated SR were significantly lower (45-55%) in the aged
compared with adult rat in the absence and presence of calmodulin.
These findings imply that changes in the intrinsic functional
properties of SR Ca2+-cycling
proteins and/or their phosphorylation-dependent regulation contribute to impaired SR function in the aging heart.
ryanodine receptor; calcium adenosinetriphosphatase; calsequestrin; phospholamban; calcium/calmodulin-dependent protein kinase
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