Abstract
BackgroundRespiratory muscle contractile performance is impaired by diabetes, mechanisms of which included altered carbohydrate and lipid metabolism, oxidative stress and changes in membrane electrophysiology. The present study examined to what extent these cellular perturbations involve changes in gene expression.Methodology/Principal FindingsDiaphragm muscle from streptozotocin-diabetic rats was analyzed with Affymetrix gene expression arrays. Diaphragm from diabetic rats had 105 genes with at least ±2-fold significantly changed expression (55 increased, 50 decreased), and these were assigned to gene ontology groups based on over-representation analysis using DAVID software. There was increased expression of genes involved in palmitoyl-CoA hydrolase activity (a component of lipid metabolism) (P = 0.037, n = 2 genes, fold change 4.2 to 27.5) and reduced expression of genes related to carbohydrate metabolism (P = 0.000061, n = 8 genes, fold change −2.0 to −8.5). Other gene ontology groups among upregulated genes were protein ubiquitination (P = 0.0053, n = 4, fold change 2.2 to 3.4), oxidoreductase activity (P = 0.024, n = 8, fold change 2.1 to 6.0), and morphogenesis (P = 0.012, n = 10, fold change 2.1 to 4.3). Other downregulated gene groups were extracellular region (including extracellular matrix and collagen) (P = 0.00032, n = 13, fold change −2.2 to −3.7) and organogenesis (P = 0.032, n = 7, fold change −2.1 to −3.7). Real-time PCR confirmed the directionality of changes in gene expression for 30 of 31 genes tested.Conclusions/SignificanceThese data indicate that in diaphragm muscle type 1 diabetes increases expression of genes involved in lipid energetics, oxidative stress and protein ubiquitination, decreases expression of genes involved in carbohydrate metabolism, and has little effect on expression of ion channel genes. Reciprocal changes in expression of genes involved in carbohydrate and lipid metabolism may change the availability of energetic substrates and thereby directly modulate fatigue resistance, an important issue for a muscle like the diaphragm which needs to contract without rest for the entire lifetime of the organism.
Highlights
Diabetes mellitus impairs respiratory muscle function in humans with type 1 diabetes, as evidenced by findings of reduced vital capacity, peak esophageal and transdiaphragmatic pressures, maximal voluntary ventilation, and ability of the respiratory muscles to maintain a target force over time [1,2,3]
Reciprocal changes in expression of genes involved in carbohydrate and lipid metabolism may change the availability of energetic substrates and thereby directly modulate fatigue resistance, an important issue for a muscle like the diaphragm which needs to contract without rest for the entire lifetime of the organism
There was a small shift towards genes involved in lipid metabolism, and a large shift away from genes involved in carbohydrate metabolism, supporting our hypothesis of diabetes altering the pattern of gene expression related to energy metabolism
Summary
Diabetes mellitus impairs respiratory muscle function in humans with type 1 diabetes, as evidenced by findings of reduced vital capacity, peak esophageal and transdiaphragmatic pressures, maximal voluntary ventilation, and ability of the respiratory muscles to maintain a target force over time [1,2,3]. Studies in animal models of type 1 diabetes have confirmed reduced strength and endurance in respiratory and other skeletal muscles [4,5,6,7,8,9,10]. Diabetes-induced skeletal muscle dysfunction likely contributes to the reduced exercise capacity of humans with both type 1 [11] and type 2 [12,13] diabetes, and may account for a portion of the increased sensation of dyspnea in humans with diabetes when ventilation or respiratory efforts are increased [3,14]. Several cellular mechanisms underlying these adverse contractile changes have been identified from biochemical and electrophysiological studies of diaphragm muscle in animal models of diabetes. Respiratory muscle contractile performance is impaired by diabetes, mechanisms of which included altered carbohydrate and lipid metabolism, oxidative stress and changes in membrane electrophysiology. The present study examined to what extent these cellular perturbations involve changes in gene expression
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