Journal Article

Short Term Exercise Induces PGC-1α, Ameliorates Inflammation and Increases Mitochondrial Membrane Proteins but Fails to Increase Respiratory Enzymes in Aging Diabetic Hearts

Laher, Ismail, Beam, Julianne, Devlin, Angela, Brown, Kirsty, Ghosh, Sanjoy, Gibson, Deanna L., Botta, Amy, Halder, Swagata, DeCoffe, Daniella

2013

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Aging / Aging - metabolism / Aging - pathology / Animal tissues / Animals / Biology / Biosynthesis / Blood glucose / Body weight / Cardiomyocytes / Cell Respiration / Chemokines / Cytokines / Diabetes / Diabetes mellitus / Diabetes Mellitus, Type 2 - enzymology / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / DNA, Mitochondrial - genetics / Downstream effects / Enzymes / Exercise / Fitness training programs / Gene expression / Genes / Glucose / Heart / Heart diseases / Hydrogen peroxide / Infiltration / Inflammation / Inflammation - genetics / Inflammation - metabolism / Inflammation - pathology / Insulin / Macrophages / Male / Medicine / Membrane proteins / Membrane Proteins - metabolism / Metabolism / Mice / Mitochondria / Mitochondrial Membranes - metabolism / Musculoskeletal system / Myocardium - enzymology / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Nitric-oxide synthase / Obesity / Oxidative Phosphorylation / Oxidative Stress / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Phosphorylation / Physical Conditioning, Animal / Physical fitness / Proteins / Respiratory enzymes / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Activation / Tumor necrosis factor-α / Up-Regulation / Weight control