Alterations in lung gene expression in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes profoundly affects gene expression in organs such as heart, skeletal muscle, kidney and liver, with areas of perturbation including carbohydrate and lipid metabolism, oxidative stress, and protein ubiquitination. Type 1 diabetes impairs lung function, but whether gene expression alterations in the lung parallel those of other tissue types is largely unexplored. METHODS: Lung from a rat model of diabetes mellitus induced by streptozotocin was subjected to gene expression microarray analysis. RESULTS: Glucose levels were 67 and 260 mg/dl (p < 0.001) in control and diabetic rats, respectively. There were 46 genes with at least ± 1.5-fold significantly altered expression (19 increases, 27 decreases). Gene ontology groups with significant over-representation among genes with altered expression included apoptosis, response to stress (p = 0.03), regulation of protein kinase activity (p = 0.04), ion transporter activity (p = 0.01) and collagen (p = 0.01). All genes assigned to the apoptosis and response to stress groups had increased expression whereas all genes assigned to the collagen group had decreased expression. In contrast, the protein kinase activity and ion transporter activity groups had genes with both increased and decreased expression. CONCLUSIONS: Gene expression in the lung is affected by type 1 diabetes in several specific areas, including apoptosis. However, the lung is resistant to changes in gene expression related to lipid and carbohydrate metabolism and oxidative stress that occur in other tissue types such as heart, skeletal muscle and kidney.

Fatigue-inducing stimulation resolves myotonia in a drug-induced model.

BACKGROUND: Slowed muscle relaxation is the contractile hallmark of myotonia congenita, a disease caused by genetic CLC-1 chloride channel deficiency, which improves with antecedent brief contractions ("warm-up phenomenon"). It is unclear to what extent the myotonia continues to dissipate during continued repetitive contractions and how this relates temporally to muscle fatigue. Diaphragm, EDL, and soleus muscles were examined in vitro during repetitive 20 Hz and 50 Hz train stimulation in a drug-induced (9-AC) rat myotonia model. RESULTS: At the onset of stimulation, 9-AC treated diaphragm and EDL muscle had markedly prolonged half relaxation and late relaxation times (range 147 to 884 ms, 894 to 1324 ms). Half relaxation and late relaxation times reached near-normal values over the 5-10 and 10-40 subsequent contractions, respectively. In both muscles myotonia declined faster during repetitive 50 Hz than 20 Hz stimulation, and much faster than the rate of force loss during fatigue at both frequencies. Soleus muscle was resistant to the myotonic effects of 9-AC. CONCLUSIONS: In a drug-induced model of mechanical myotonia, fatigue-inducing stimulation resolves the myotonia, which furthermore appears to be independent from the development of muscle fatigue.

Differential expression of lipid and carbohydrate metabolism genes in upper airway versus diaphragm muscle.

STUDY OBJECTIVES: Contractile properties of upper airway muscles influence upper airway patency, an issue of particular importance for subjects with obstructive sleep apnea. Expression of genes related to cellular energetics is, in turn, critical for the maintenance of contractile integrity over time during repetitive activation. We tested the hypothesis that sternohyoid has lower expression of genes related to lipid and carbohydrate energetic pathways than the diaphragm. METHODS: Sternohyoid and diaphragm from normal adult rats were examined with gene expression arrays. Analysis focused on genes belonging to Gene Ontology (GO) groups carbohydrate metabolism and lipid metabolism. RESULTS: There were 433 genes with at least +/- 2-fold significant differential expression between sternohyoid and diaphragm, of which 192 had sternohyoid > diaphragm and 241 had diaphragm > sternohyoid expression. Among genes with higher sternohyoid expression, there was over-representation of the GO group carbohydrate metabolism (P = 0.0053, n = 13 genes, range of differential expression 2.1- to 6.2-fold) but not lipid metabolism (P = 0.44). Conversely, among genes with higher diaphragm expression, there was over-representation of the GO group lipid metabolism (P = 0.0000065, n = 32 genes, range of differential expression 2.0- to 37.9-fold) but not carbohydrate metabolism (P = 0.23). Nineteen genes with diaphragm > sternohyoid expression were related to fatty acid metabolism (P = 0.000000058), in particular fatty acid beta oxidation and biosynthesis in the mitochondria. CONCLUSIONS: Sternohyoid has much lower gene expression than diaphragm for mitochondrial enzymes that participate in fatty acid oxidation and biosynthesis. This likely contributes to the lower fatigue resistance of pharyngeal upper airway muscles compared with the diaphragm.

Contrast between cardiac left ventricle and diaphragm muscle in expression of genes involved in carbohydrate and lipid metabolism.

The heart and diaphragm both need appropriate metabolic machinery to ensure long-term energy supplies, as they must contract rhythmically without cessation for the entire lifetime of the organism to ensure homeostasis of oxygen and carbon dioxide exchange. However, their energy requirements differ due to disparities in mechanical loads. Understanding how these two muscles converge and diverge in their approaches to meeting their metabolic demands may suggest novel strategies for improving cardiac and skeletal muscle long-term performance in health and disease. To assess this at a transcriptional level, expression of genes involved in carbohydrate and lipid metabolism was assessed using microarrays in rats. There were 594 genes with >2-fold differential expression between left ventricle of the heart and diaphragm; 307 were expressed heart>diaphragm and 287 diaphragm>heart. Assignment to gene ontology groups revealed over-representation for "carbohydrate metabolism" (P=0.005, n=32 genes or 5.4% of all genes with differential expression) and "lipid metabolism" (P=0.0012, n=48 genes or 8.1% of all genes with differential expression). For carbohydrate there were 14 genes with heart>diaphragm and 18 genes with diaphragm>heart, and for lipid there were 30 genes with heart>diaphragm and 18 genes with diaphragm>heart. The magnitude of differential expression between heart and diaphragm ranged up to 30-fold for carbohydrate and up to 59-fold for lipid. Carbohydrate-related genes were almost all involved in energy metabolism (e.g. Pfkm, Pgm1, Pgam1, Pfkfb1, Pfkfb2), whereas lipid-related genes were involved in energetics as well as other cellular processes; for both groups this included genes involved in rate-limiting metabolic steps. Data thus indicate that diaphragm and heart have both shared and differential transcriptional strategies for ensuring long-term energy supplies, with a relative favoring of lipid metabolism in the heart and carbohydrate metabolism in the diaphragm.