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:Preclinical models of type 1 diabetes mellitus exhibit marked declines in skeletal muscle health including significant impairments in muscle repair. The present study investigated, for the first time, whether muscle repair was altered in young adults with uncomplicated type 1 diabetes (T1D) following damaging exercise.In this cohort study, eighteen physically-active young adults (M=22.1, SEM=0.9 years) with T1D (n, male/female=4/5; MHbA1c= 58, SEMHbA1c=5.9 mmol/mol) and without T1D (n, male/female=4/5) performed 300 unilateral eccentric contractions (90°s-1) of the knee extensors. Prior to exercise, at 48-hours and at 96-hours after exercise, participants gave a venous blood sample and vastus lateralis biopsy and performed a maximal voluntary isometric knee extension. Skeletal muscle extracellular matrix content, and satellite cell content/proliferation were assessed by immunofluorescence. Transmission electron microscopy was used to quantify ultrastructural damage.Maximal isometric strength was comparable between T1D and their sex-matched control group prior to exercise for both sexes. Immediately following damaging exercise, strength was decreased in both groups but there was a moderate effect size for lower strength during recovery in the T1D group at both 48-hours and 96-hours. Serum creatine kinase, an indicator of muscle damage, was moderately higher in T1D participants compared to controls at rest, and exhibited a small elevation 96-hours after exercise. Immunofluorescence analyses showed satellite cell content was lower at all timepoints in those with type 1 diabetes. T1D participants demonstrated a moderate delay in satellite cell proliferation (as assessed by Pax7+/Ki67+ nuclei counts) after exercise, reaching peak levels of proliferation 48-hours after control participants. Despite these differences, those with T1D did not exhibit greater ultrastructural muscle damage than controls as assessed by electron microscopy. Finally, a transcriptomic investigation of T1D muscle revealed several networks of dysregulated genes involving RNA translation as well as mitochondrial respiration function, providing potential explanations for previous observations of mitochondrial dysfunction in similar T1D cohorts. Our novel findings indicate that skeletal muscle from physically active, young adults with moderately controlled T1D may have a reduced ability to handle, and repair from, damaging exercise. While larger cohort studies are clearly needed, these results suggest that those with T1D may require longer recovery times following damaging exercise.

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.

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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