Background: Dietary n-6 polyunsaturated fats (n-6 PUFA) like linoleic acid (LA) may worsen cardiac remodeling after injury. Results: Excess LA increased cardiac collagen I/III ratio and lysyl oxidase causing early diastolic dysfunction. In vitro experiments in fibroblasts with genetic manipulation confirmed such mechanisms. Conclusion: LA promotes noncompliant collagen and cardiac stiffening. Significance: This study demonstrates a novel, cardiac-specific lipotoxic pathway of n-6 PUFAs.
PGC-1α, a transcriptional coactivator, controls inflammation and mitochondrial gene expression in insulin-sensitive tissues following exercise intervention. However, attributing such effects to PGC-1α is counfounded by exercise-induced fluctuations in blood glucose, insulin or bodyweight in diabetic patients. The goal of this study was to investigate the role of PGC-1α on inflammation and mitochondrial protein expressions in aging db/db mice hearts, independent of changes in glycemic parameters. In 8-month-old db/db mice hearts with diabetes lasting over 22 weeks, short-term, moderate-intensity exercise upregulated PGC-1α without altering body weight or glycemic parameters. Nonetheless, such a regimen lowered both cardiac (macrophage infiltration, iNOS and TNFα) and systemic (circulating chemokines and cytokines) inflammation. Curiously, such an anti-inflammatory effect was also linked to attenuated expression of downstream transcription factors of PGC-1α such as NRF-1 and several respiratory genes. Such mismatch between PGC-1α and its downstream targets was associated with elevated mitochondrial membrane proteins like Tom70 but a concurrent reduction in oxidative phosphorylation protein expressions in exercised db/db hearts. As mitochondrial oxidative stress was predominant in these hearts, in support of our in vivo data, increasing concentrations of H2O2 dose-dependently increased PGC-1α expression while inhibiting expression of inflammatory genes and downstream transcription factors in H9c2 cardiomyocytes in vitro. We conclude that short-term exercise-induced oxidative stress may be key in attenuating cardiac inflammatory genes and impairing PGC-1α mediated gene transcription of downstream transcription factors in type 2 diabetic hearts at an advanced age.
Moderate exercise improves cardiac antioxidant status in young humans and animals with Type-2 diabetes (T2D). Given that both diabetes and advancing age synergistically decrease antioxidant expression in most tissues, it is unclear whether exercise can upregulate cardiac antioxidants in chronic animal models of T2D. To this end, 8-month-old T2D and normoglycemic mice were exercised for 3 weeks, and cardiac redox status was evaluated. As expected, moderate exercise increased cardiac antioxidants and attenuated oxidative damage in normoglycemic mice. In contrast, similar exercise protocol in 8-month-old db/db mice worsened cardiac oxidative damage, which was associated with a specific dysregulation of glutathione (GSH) homeostasis. Expression of enzymes for GSH biosynthesis [γ-glutamylcysteine synthase, glutathione reductase] as well as for GSH-mediated detoxification (glutathione peroxidase, glutathione-S-transferase) was lower, while toxic metabolites dependent on GSH for clearance (4-hydroxynonenal) were increased in exercised diabetic mice hearts. To validate GSH loss as an important factor for such aggravated damage, daily administration of GSH restored cardiac GSH levels in exercised diabetic mice. Such supplementation attenuated both oxidative damage and fibrotic changes in the myocardium. Expression of transforming growth factor beta (TGF-β) and its regulated genes which are responsible for such profibrotic changes were also attenuated with GSH supplementation. These novel findings in a long-term T2D animal model demonstrate that short-term exercise by itself can deplete cardiac GSH and aggravate cardiac oxidative stress. As GSH administration conferred protection in 8-month-old diabetic mice undergoing exercise, supplementation with GSH-enhancing agents may be beneficial in elderly diabetic patients undergoing exercise.
Low‐intensity exercise improves cardiac antioxidants in young animals irrespective of metabolic changes in type 2 diabetes (T2D). As diabetes and aging synergistically can decrease antioxidants, if exercises can increase antioxidants in mature T2D hearts, is unknown. 8‐month old db/db and wild‐type (WT) mice were moderately exercised for 3 weeks, and cardiac redox regulation was evaluated. Without altering metabolic status, exercise increased cardiac antioxidants and attenuated stress in mature WT mice. In contrast, exercise in db/db mice worsened oxidative damage, which was not explained by superoxide dismutase or catalase activities. Instead, loss of the antioxidant, glutathione (GSH) was noted. Further, GSH biosynthesis [γ‐glutamylcysteine synthase] and recycling [NADPH/NADP, glutathione reductase] were impaired while GSH‐dependent stress (GPX, 4‐hydroxynonenal, TGF‐β) was increased in these hearts. To validate the causal role for GSH, exercising db/db mice were administered exogenous GSH, which attenuated cardiac damage. This study shows that unlike younger animals, short‐term exercise may induce oxidative stress in mature animals and GSH supplementation can inhibit such stress in these hearts. Therefore, recent assertions of detrimental impact of antioxidants during exercise in healthy individuals should be extrapolated with caution in mature T2D patients undergoing exercise.
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