Stable microtubules contribute to cardiac dysfunction in the streptozotocin-induced model of type 1 diabetes in the rat |
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Authors: | Holly Shiels Anthony O’Connell M Anwar Qureshi F Christopher Howarth Ed White Sarah Calaghan |
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Institution: | (1) Research Institute of Membrane and Systems Biology, University of Leeds, Worsley Building, Leeds , LS2 9JT, UK;(2) Faculty of Life Sciences, Core Technology Facility, University of Manchester, 46 Grafton St, Manchester , M13 9PT, UK;(3) Department of Physiology, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates |
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Abstract: | Cardiac microtubule stability is increased in the streptozotocin (STZ) model of type 1 diabetes. Here, we investigate the
reason for increased microtubule stability, and the functional consequences of stable microtubule disruption. Ventricular
myocytes were isolated from rats at 8–12 weeks after injection of STZ. A 10% increase in microtubule density, but no difference
in the ratio of microtubule-associated protein 4 (MAP4) to tubulin was seen in myocytes from STZ rats. Functionally, STZ myocytes
showed a tendency for reduced shortening and intracellular Ca2+ (Ca2+]
i
) transient amplitude, and a significant prolongation of time to peak (ttp) shortening and Ca2+]
i
. Although microtubules in STZ myocytes were less sensitive to the microtubule disruptor nocodazole (NOC; 33 μM) than control
myocytes, we only saw marked functional consequences of microtubule disruption by NOC in myocytes from diabetic animals. NOC
increased shortening and Ca2+]
i
transient amplitude in STZ myocytes by 45 and 24%, respectively (compared with 4 and 6% in controls). Likewise, NOC decreased
ttp shortening and Ca2+]
i
only in STZ myocytes, such that these parameters were no longer different between the two groups. In conclusion, stable microtubules
in diabetes are not associated with an increase in MAP4, but are functionally relevant to cardiac dysfunction in diabetes,
regulating both Ca2+]
i
and shortening.
Holly Shiels and Anthony O’Connell are equal first authorship. |
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Keywords: | calcium cardiac function cardiomyocyte contraction cytoskeleton diabetes |
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