Stable microtubules contribute to cardiac dysfunction in the streptozotocin-induced model of type 1 diabetes in the rat.
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 microM) 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.
Shiels
Holly
H
Faculty of Life Sciences, Core Technology Facility, University of Manchester, 46 Grafton St, Manchester , M13 9PT, UK.
O'Connell
Anthony
A
Qureshi
M Anwar
MA
Howarth
F Christopher
FC
White
Ed
E
Calaghan
Sarah
S
D000818:Animals; D009202:Cardiomyopathies / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D015739:Nocodazole