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. 2015 Jan;8(1):188-97.
doi: 10.1161/CIRCHEARTFAILURE.114.001540. Epub 2014 Dec 11.

Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling

Jarrod A Call  1 , Kristopher H Chain  1 , Kyle S Martin  1 , Vitor A Lira  1 , Mitsuharu Okutsu  1 , Mei Zhang  1 , Zhen Yan  2
Affiliations

Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling

Jarrod A Call et al. Circ Heart Fail. 2015 Jan.

Abstract

Background: Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes mellitus. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin-induced diabetic cardiomyopathy.

Methods and results: Exercise training promotes EcSOD expression in skeletal muscle and provides protection against diabetic cardiomyopathy; however, it is not known if enhanced expression of EcSOD in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice are protected from cardiac hypertrophy, fibrosis, and dysfunction under the condition of type 1 diabetes mellitus induced by streptozotocin injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting that enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in transgenic mice displayed significantly reduced oxidative stress, aberrant cell signaling, and inflammatory cytokine expression compared with wild-type mice under the same diabetic condition.

Conclusions: Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate streptozotocin-induced diabetic cardiomyopathy through attenuation of oxidative stress, aberrant cell signaling, and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes mellitus.

Keywords: antioxidants; cardiomyocyte; diabetic cardiomyopathies; exercise; hypertrophy; oxidative stress.

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Figures

Figure 1
Figure 1. Enhanced expression of EcSOD in skeletal muscle redistributes to the heart
(A) Four weeks of voluntary wheel running affected EcSOD expression in the hearts and serum of exercise trained WT (Ex; n=9) mice compared to WT sedentary (Sed; n=9) controls, and EcSOD levels in the heart were independent of mRNA expression. Student’s t-test, * denotes P<0.05. (B) EcSOD levels were 11-fold greater in the serum and 4-fold greater in the hearts of EcSOD TG mice, independent of STZ (n=12) compared to WT littermate controls, independent of STZ (n=12), and EcSOD levels in the heart were independent of mRNA expression. ANOVA, group effect for genotype, *** denotes P<0.001. (C) EcSOD protein was enriched near the endothelial cells in the heart, and had greater presence within individual cardiomyocytes in EcSOD TG mice compared to WT littermate controls. Scale bar is 25 µm. Graphical bars are means ± SE.
Figure 2
Figure 2. Enhanced EcSOD expression in skeletal muscle prevents STZ-induced impairment in cardiac function
(A) Representative M-mode echocardiograph heart images. (B–C) Graphical representation showing ejection fraction and fractional shortening calculated from echocardiograph analysis. (D) Graphical representation of in vivo, fully conscious heart rate from electrocardiograph analysis. WT-Con, n=6; WT-STZ, n=11; TG-Con, n=6; TG-STZ, n=12. ANOVA, significant interaction, followed by Tukey’s HSD post-hoc test *, **, and *** denote P<0.05, P<0.01, and P<0.001, respectively. Bars are means ± SE.
Figure 3
Figure 3. Enhanced EcSOD expression in skeletal muscle mitigates STZ-induced cardiac hypertrophy and fibrosis
(A) Representative heart images stained with hemotoxylin and eosin to identify individual cardiomyocytes. (B) Graphic representation of individual cardiomyocyte cross-sectional area. (C) Cardiomyocyte size frequency distributions based on cross-sectional area. WT-CON, black bar with dotted area; WT-STZ, red bar; TG-CON, grey area; TG-STZ, green bar. Note the rightward distribution shift of the WT-STZ fibers relative to all other groups. Among these mice there was an abnormally large amount of large fibers (>300 µm). (D) Representative heart images stained for fibrotic tissue deposition by sirius red. (E) Graphical representation of collagen staining. WT-Con, n=6; WT-STZ, n=11; TG-Con, n=6; TG-STZ, n=12. ANOVA, significant interaction, followed by Tukey’s HSD post-hoc test ** and *** denote P<0.01 and P<0.001.
Figure 4
Figure 4. Enhanced EcSOD expression in skeletal muscle protects against STZ-induced oxidative damage and aberrant signaling in the heart
Representative immunoblots and graphical representation of statistical analysis is shown for 4-HNE (A) and protein carbonylation (B). Staining was normalized by tubulin and is shown relative to WT-CON. WT-Con, n=6; WT-STZ, n=11; TG-Con, n=6; TG-STZ, n=12. ANOVA, significant interaction, followed by Tukey’s HSD post-hoc test * and *** denotes P<0.05 and P<0.001. Bars are means ± SE.
Figure 5
Figure 5. Enhanced EcSOD expression in skeletal muscle protects against STZ-induced aberrant signaling in the heart
(A) STZ-induced activation of calcineurin and p38 MAPK in hearts is mitigated in EcSOD TG mice. (B) EcSOD alleviates STZ-induced TNF-α and ANP mRNA expression. WT-Con, n=6; WT-STZ, n=11; TG-Con, n=6; TG-STZ, n=12. ANOVA, significant interaction, followed by Tukey’s HSD post-hoc test * denotes P<0.05. Bars are means ± SE.
Figure 6
Figure 6. Schematic illustration of the role of enhanced EcSOD expression in skeletal muscle in protection against DCM
Enhanced EcSOD expression in skeletal muscle leads to increased distribution of EcSOD via the circulation to cardiomyocytes through either capillary endothelium or endocardial endothelium. Increased EcSOD in the cardiomyocytes mitigates hyperglycemia-induced oxidative stress hence preventing contractile dysfunction and maladaptation and blocking the pathogenesis of DCM.
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