Dataset Information

Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus.

ABSTRACT: Skeletal muscle resistance to insulin is related to accumulation of lipid-derived products, but it is not clear whether this accumulation is caused by skeletal muscle mitochondrial dysfunction. Diabetes and obesity are reported to have a selective effect on the function of subsarcolemmal and interfibrillar mitochondria in insulin-resistant skeletal muscle. The current study investigated the role of the subpopulations of mitochondria in the pathogenesis of insulin resistance in the absence of obesity. A non-obese spontaneous rat model of type 2 diabetes mellitus, (Goto-Kakizaki), was used to evaluate function and biochemical properties in both populations of skeletal muscle mitochondria. In subsarcolemmal mitochondria, minor defects are observed whereas in interfibrillar mitochondria function is preserved. Subsarcolemmal mitochondria defects characterized by a mild decline of oxidative phosphorylation efficiency are related to ATP synthase and structural alterations of inner mitochondria membrane but are considered unimportant because of the absence of defects upstream as shown with polarographic and spectrophometric assays. Fatty acid transport and oxidation is preserved in both population of mitochondria, whereas palmitoyl-CoA increased 25% in interfibrillar mitochondria of diabetic rats. Contrary to popular belief, these data provide compelling evidence that mitochondrial function is unaffected in insulin-resistant skeletal muscle from T2DM non-obese rats.

SUBMITTER: Lai N

PROVIDER: S-EPMC5574550 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus.

Lai Nicola N Kummitha China C Hoppel Charles C

PloS one 20170829 8

Skeletal muscle resistance to insulin is related to accumulation of lipid-derived products, but it is not clear whether this accumulation is caused by skeletal muscle mitochondrial dysfunction. Diabetes and obesity are reported to have a selective effect on the function of subsarcolemmal and interfibrillar mitochondria in insulin-resistant skeletal muscle. The current study investigated the role of the subpopulations of mitochondria in the pathogenesis of insulin resistance in the absence of obe ...[more]

PMID: 28850625

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Project description:Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans. Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests. Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPAR?) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3?), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPAR? pathway and GLUT4, sustained inhibition of p-GSK-3? and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples. Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.

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Dataset Information

Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus.

Publications

Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus.

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