title: Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet.
abstract: Given the clinical prevalence of type 2 diabetes and obesity and their association with high mortality linked to cardiovascular disease, the aim of the study was to investigate the effects of feeding type 2 diabetic Goto-Kakizaki (GK) rats either high- or low-fat diets on cardiomyocyte structure and function. The GK rats were fed either a high-fat diet (HFD) or a low-fat diet (LFD) from the age of 2 months for a period of 7 months. The GK-HFD rats gained more weight, ate less food and drank less water compared with GK-LFD rats. At 7 months, non-fasting blood glucose was higher in GK-LFD (334 ± 35 mg dl(-1)) compared with GK-HFD rats (235 ± 26 mg dl(-1)). Feeding GK rats with a HFD had no significant effect on glucose clearance following a glucose challenge. Time-to-peak (t(peak)) shortening was reduced in myocytes from GK-HFD (131.8 ± 2.1 ms) compared with GK-LFD rats (144.5 ± 3.0 ms), and time-to-half (t(1/2)) relaxation of shortening was also reduced in myocytes from GK-HFD (71.7 ± 6.9 ms) compared with GK-LFD rats (86.1 ± 3.6 ms). The HFD had no significant effect on the amplitude of shortening. The HFD had no significant effect on t(peak), t(1/2) decay, amplitude of the Ca(2+) transient, myofilament sensitivity to Ca(2+), sarcoplasmic reticulum Ca(2+) content, fractional release of Ca(2+) and the rate of Ca(2+) uptake. Structurally, ventricular myocytes from GK-HFD rats showed extensive mitochondrial lesions, including swelling, loss of cristae, and loss of inner and outer membranes, resulting in gross vacuolarization and deformation of ventricular mitochondria with a subsequent reduction in mitochondrial density. Expression of genes encoding various L-type Ca(2+) channel proteins (Cacnb2) and cardiac muscle proteins (Myl2 and Atp2a1) were downregulated in GK-HFD compared with GK-LFD rats. Structural lesions and changed expression of genes encoding various cardiac muscle proteins might partly underlie the altered time course of myocyte shortening and relaxation in myocytes from GK-HFD compared with GK-LFD rats.
authors.affiliation: Department of Physiology, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. chris.howarth@uaeu.ac.ae
authors.forename: Frank C
authors.initials: FC
authors.lastname: Howarth
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Qureshi
authors.forename: Zahra H H
authors.initials: ZH
authors.lastname: Sobhy
authors.forename: Khatija
authors.initials: K
authors.lastname: Parekh
authors.forename: Salem R R K D
authors.initials: SR
authors.lastname: Yammahi
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Adrian
authors.forename: Ernest
authors.initials: E
authors.lastname: Adeghate
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018752:Diet, Fat-Restricted / Q000379:methods; D059305:Diet, High-Fat / Q000379:methods; D015536:Down-Regulation; D005215:Fasting / Q000378:metabolism; D015870:Gene Expression; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D009210:Myofibrils / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: C506945:Atp2a1 protein, rat; D001786:Blood Glucose; C491527:Cacnb2 protein, rat; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium