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Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD).

Mosqueira M, Willmann G, Ruohola-Baker H, Khurana TS - PLoS ONE (2010)

Bottom Line: To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level).Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT.Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD.

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Related in: MedlinePlus

Venn diagram of comparison gene expression profile between dmDys and WT flies exposed to CH.From 1281 differentially expressed genes in dmDys and 56 in WT flies, 20 genes were found to be in common; among them, 10 genes were concordantly regulated in both profiles, while 10 were discordantly regulated in the profiles.
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pone-0013450-g005: Venn diagram of comparison gene expression profile between dmDys and WT flies exposed to CH.From 1281 differentially expressed genes in dmDys and 56 in WT flies, 20 genes were found to be in common; among them, 10 genes were concordantly regulated in both profiles, while 10 were discordantly regulated in the profiles.

Mentions: Comparing hypoxia-induced gene changes in dmDys and WT flies, we found 20 common genes (Figure 5), of which 10 genes were up-regulated in both profiles (CH-dmDys and CH-WT), and 10 genes were discordantly regulated in that they were down-regulated in CH-dmDys but up-regulated in CH-WT. Interestingly, 8 out of 10 genes in the disparate group belong to HSP family (Table 1). To determine the changes in gene expression caused only by the absence of dystrophin, we compare the gene expression profiles obtained from dmDys vs. WT, both under normoxic conditions. In this analysis, we found 208 genes differentially expressed, in which 114 genes were up-regulated and 94 were down-regulated in dmDys (Table S9). Interestedly, among the 114 up-regulated genes we found 8 Hsp genes, which were the same as those that were down-regulated in dmDys exposed to CH, as described above (Hsp23, Hsp26, Hsp27, Hsp67Bb, Hsp68, Hsp70Aa, Hsp70Bbb and Hsp70Bc).


Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD).

Mosqueira M, Willmann G, Ruohola-Baker H, Khurana TS - PLoS ONE (2010)

Venn diagram of comparison gene expression profile between dmDys and WT flies exposed to CH.From 1281 differentially expressed genes in dmDys and 56 in WT flies, 20 genes were found to be in common; among them, 10 genes were concordantly regulated in both profiles, while 10 were discordantly regulated in the profiles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958114&req=5

pone-0013450-g005: Venn diagram of comparison gene expression profile between dmDys and WT flies exposed to CH.From 1281 differentially expressed genes in dmDys and 56 in WT flies, 20 genes were found to be in common; among them, 10 genes were concordantly regulated in both profiles, while 10 were discordantly regulated in the profiles.
Mentions: Comparing hypoxia-induced gene changes in dmDys and WT flies, we found 20 common genes (Figure 5), of which 10 genes were up-regulated in both profiles (CH-dmDys and CH-WT), and 10 genes were discordantly regulated in that they were down-regulated in CH-dmDys but up-regulated in CH-WT. Interestingly, 8 out of 10 genes in the disparate group belong to HSP family (Table 1). To determine the changes in gene expression caused only by the absence of dystrophin, we compare the gene expression profiles obtained from dmDys vs. WT, both under normoxic conditions. In this analysis, we found 208 genes differentially expressed, in which 114 genes were up-regulated and 94 were down-regulated in dmDys (Table S9). Interestedly, among the 114 up-regulated genes we found 8 Hsp genes, which were the same as those that were down-regulated in dmDys exposed to CH, as described above (Hsp23, Hsp26, Hsp27, Hsp67Bb, Hsp68, Hsp70Aa, Hsp70Bbb and Hsp70Bc).

Bottom Line: To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level).Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT.Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys).

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD.

Show MeSH
Related in: MedlinePlus