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Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy.

Lee YS, Lehar A, Sebald S, Liu M, Swaggart KA, Talbot CC, Pytel P, Barton ER, McNally EM, Lee SJ - Hum. Mol. Genet. (2015)

Bottom Line: As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss.Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(-/-) mice, indicating possible muscle damage induced by hypertrophy.These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics and.

No MeSH data available.


Related in: MedlinePlus

Analysis of global gene expression patterns in wt, Dysf−/−, F66, F66; Dysf−/− and ACVR2B/Fc-injected wt and Dysf−/− mice. (A) PCA mapping analysis. Affymetrix Mouse Exon 1.0 ST arrays were hybridized in three biologically independent experiments with RNA from quadriceps muscles of wt (blue circle), Dysf−/− (blue diamond), F66 (green circle), F66;Dysf−/− (purple diamond) mice and ACVR2B/Fc-injected wt (orange circle) and Dysf−/− (red diamond) mice (three replicates in six different groups: 18 samples). Note that F66;Dysf−/− and F66 groups are well segregated from each other and from the other remaining groups in PCA mappings. First component (PC # 1) and second component (PC # 2) data are shown. (B) Heat map corresponding to differentially expressed genes (P < 0.01). Data represent averages of three independent experiments in red (enriched) or blue (depleted). (C) Heat map corresponding to genes related to dysferlin function. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8. (D) Heat map corresponding to genes encoding components of the myostatin/TGF-β signaling pathway. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8.
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DDV288F4: Analysis of global gene expression patterns in wt, Dysf−/−, F66, F66; Dysf−/− and ACVR2B/Fc-injected wt and Dysf−/− mice. (A) PCA mapping analysis. Affymetrix Mouse Exon 1.0 ST arrays were hybridized in three biologically independent experiments with RNA from quadriceps muscles of wt (blue circle), Dysf−/− (blue diamond), F66 (green circle), F66;Dysf−/− (purple diamond) mice and ACVR2B/Fc-injected wt (orange circle) and Dysf−/− (red diamond) mice (three replicates in six different groups: 18 samples). Note that F66;Dysf−/− and F66 groups are well segregated from each other and from the other remaining groups in PCA mappings. First component (PC # 1) and second component (PC # 2) data are shown. (B) Heat map corresponding to differentially expressed genes (P < 0.01). Data represent averages of three independent experiments in red (enriched) or blue (depleted). (C) Heat map corresponding to genes related to dysferlin function. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8. (D) Heat map corresponding to genes encoding components of the myostatin/TGF-β signaling pathway. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8.

Mentions: Finally, we used microarray analysis to examine global transcriptional changes in the quadriceps muscles from wt, Dysf−/−, F66, F66;Dysf−/− mice and ACVR2B/Fc-injected wt and Dysf−/− mice at 10 weeks of age. By principal components analysis (PCA) mapping, the F66;Dysf−/− and F66 groups were well segregated from each other as well as the other groups (Fig. 4A). The differences of global gene expression patterns among the six groups were also seen in their heat maps (Fig. 4B). As expected, two classes of genes that showed clear differences among the various groups were genes related to dysferlin function and genes encoding components of the myostatin/TGF-β signaling pathway (Fig. 4C and D). Seven genes related to dysferlin function, Dysf, Myof, Anxa1, Anxa2, S100a4, S100a10 and Capn3, were visualized in Volcano plots in five different comparisons (Supplementary Material, Fig. S2); Myof, Anxa1, Anxa2, S100a4 and S100a10 were significantly upregulated by Fst overexpression while Capn3 was significantly downregulated by Fst overexpression. Mstn, Gdf11, Inha and Inhba genes encode proteins that have been shown to be bound and inhibited by Fst and ACVR2B/Fc. While there was no significant change in Dysf−/− compared with wt, Fst overexpression and ACVR2B/Fc administration induced the dramatic changes of expression levels of these genes in both Dysf−/− and wt (Supplementary Material, Fig. S3); Gdf11 was upregulated slightly in ACVR2B/Fc-injected wt and ACVR2B/Fc-injected Dysf−/− and significantly in F66 and F66;Dysf−/−; Mstn was downregulated slightly in ACVR2B/Fc-injected Dysf−/− compared with Dysf−/− and significantly in F66;Dysf−/− compared with Dysf−/−. The full list of genes with fold changes is given in Supplementary Material, Table S8.Figure 4.


Muscle hypertrophy induced by myostatin inhibition accelerates degeneration in dysferlinopathy.

Lee YS, Lehar A, Sebald S, Liu M, Swaggart KA, Talbot CC, Pytel P, Barton ER, McNally EM, Lee SJ - Hum. Mol. Genet. (2015)

Analysis of global gene expression patterns in wt, Dysf−/−, F66, F66; Dysf−/− and ACVR2B/Fc-injected wt and Dysf−/− mice. (A) PCA mapping analysis. Affymetrix Mouse Exon 1.0 ST arrays were hybridized in three biologically independent experiments with RNA from quadriceps muscles of wt (blue circle), Dysf−/− (blue diamond), F66 (green circle), F66;Dysf−/− (purple diamond) mice and ACVR2B/Fc-injected wt (orange circle) and Dysf−/− (red diamond) mice (three replicates in six different groups: 18 samples). Note that F66;Dysf−/− and F66 groups are well segregated from each other and from the other remaining groups in PCA mappings. First component (PC # 1) and second component (PC # 2) data are shown. (B) Heat map corresponding to differentially expressed genes (P < 0.01). Data represent averages of three independent experiments in red (enriched) or blue (depleted). (C) Heat map corresponding to genes related to dysferlin function. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8. (D) Heat map corresponding to genes encoding components of the myostatin/TGF-β signaling pathway. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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DDV288F4: Analysis of global gene expression patterns in wt, Dysf−/−, F66, F66; Dysf−/− and ACVR2B/Fc-injected wt and Dysf−/− mice. (A) PCA mapping analysis. Affymetrix Mouse Exon 1.0 ST arrays were hybridized in three biologically independent experiments with RNA from quadriceps muscles of wt (blue circle), Dysf−/− (blue diamond), F66 (green circle), F66;Dysf−/− (purple diamond) mice and ACVR2B/Fc-injected wt (orange circle) and Dysf−/− (red diamond) mice (three replicates in six different groups: 18 samples). Note that F66;Dysf−/− and F66 groups are well segregated from each other and from the other remaining groups in PCA mappings. First component (PC # 1) and second component (PC # 2) data are shown. (B) Heat map corresponding to differentially expressed genes (P < 0.01). Data represent averages of three independent experiments in red (enriched) or blue (depleted). (C) Heat map corresponding to genes related to dysferlin function. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8. (D) Heat map corresponding to genes encoding components of the myostatin/TGF-β signaling pathway. Relative expression levels (fold change compared to wt) are shown in Supplementary Material, Table S8.
Mentions: Finally, we used microarray analysis to examine global transcriptional changes in the quadriceps muscles from wt, Dysf−/−, F66, F66;Dysf−/− mice and ACVR2B/Fc-injected wt and Dysf−/− mice at 10 weeks of age. By principal components analysis (PCA) mapping, the F66;Dysf−/− and F66 groups were well segregated from each other as well as the other groups (Fig. 4A). The differences of global gene expression patterns among the six groups were also seen in their heat maps (Fig. 4B). As expected, two classes of genes that showed clear differences among the various groups were genes related to dysferlin function and genes encoding components of the myostatin/TGF-β signaling pathway (Fig. 4C and D). Seven genes related to dysferlin function, Dysf, Myof, Anxa1, Anxa2, S100a4, S100a10 and Capn3, were visualized in Volcano plots in five different comparisons (Supplementary Material, Fig. S2); Myof, Anxa1, Anxa2, S100a4 and S100a10 were significantly upregulated by Fst overexpression while Capn3 was significantly downregulated by Fst overexpression. Mstn, Gdf11, Inha and Inhba genes encode proteins that have been shown to be bound and inhibited by Fst and ACVR2B/Fc. While there was no significant change in Dysf−/− compared with wt, Fst overexpression and ACVR2B/Fc administration induced the dramatic changes of expression levels of these genes in both Dysf−/− and wt (Supplementary Material, Fig. S3); Gdf11 was upregulated slightly in ACVR2B/Fc-injected wt and ACVR2B/Fc-injected Dysf−/− and significantly in F66 and F66;Dysf−/−; Mstn was downregulated slightly in ACVR2B/Fc-injected Dysf−/− compared with Dysf−/− and significantly in F66;Dysf−/− compared with Dysf−/−. The full list of genes with fold changes is given in Supplementary Material, Table S8.Figure 4.

Bottom Line: As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss.Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf(-/-) mice, indicating possible muscle damage induced by hypertrophy.These findings suggest that depending on the disease context, inducing muscle hypertrophy by myostatin blockade may have detrimental effects, which need to be weighed against the potential gains in muscle growth and decreased fibrosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics and.

No MeSH data available.


Related in: MedlinePlus