Limits...
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

Hypertrophy induced by Fst transgene expression accelerates muscular degeneration in Dysf−/− mice. (A–D) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in Dysf−/− mice as a function of age. Graphs were made from the data shown in Supplementary Material, Table S1. Note the dramatic loss of muscle mass induced by F66 in Dysf−/− mice beginning at 4 months of age. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.05 versus Dysf−/−; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (E–H) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in mdx mice as a function of age. Note that F66 did not induce muscle loss in mdx mice. Graphs were made from the data shown in Supplementary Material, Table S2. **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus mdx; ###P < 0.001 versus mdx; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (I) Sections were stained with H&E, von Kossa (to highlight calcified fibers) and Masson's trichrome (to highlight areas of fibrosis). The F66;Dysf−/− mice showed the pathologic changes including fibrosis and centrally nucleated muscle fibers, even at 10 weeks of age, when Dysf−/− mice showed no distinct muscular degeneration. The F66;mdx mice showed the pathologic changes similar to mdx mice. Scale bar represents 50 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581601&req=5

DDV288F1: Hypertrophy induced by Fst transgene expression accelerates muscular degeneration in Dysf−/− mice. (A–D) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in Dysf−/− mice as a function of age. Graphs were made from the data shown in Supplementary Material, Table S1. Note the dramatic loss of muscle mass induced by F66 in Dysf−/− mice beginning at 4 months of age. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.05 versus Dysf−/−; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (E–H) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in mdx mice as a function of age. Note that F66 did not induce muscle loss in mdx mice. Graphs were made from the data shown in Supplementary Material, Table S2. **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus mdx; ###P < 0.001 versus mdx; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (I) Sections were stained with H&E, von Kossa (to highlight calcified fibers) and Masson's trichrome (to highlight areas of fibrosis). The F66;Dysf−/− mice showed the pathologic changes including fibrosis and centrally nucleated muscle fibers, even at 10 weeks of age, when Dysf−/− mice showed no distinct muscular degeneration. The F66;mdx mice showed the pathologic changes similar to mdx mice. Scale bar represents 50 µm.

Mentions: To investigate the effect of blocking myostatin signaling in the setting of dysferlinopathy, we used both genetic and pharmacological approaches in mice. For the genetic approach, we overexpressed follistatin (Fst), which is a secreted protein capable of binding and inhibiting various members of the TGF-β superfamily, including myostatin (20). For these studies, we utilized a transgenic mouse line (F66) in which we had expressed Fst under the control of a skeletal muscle-specific myosin light chain promoter/enhancer (20). As shown in Figure 1A–D and Supplementary Material, Table S1, and as we reported previously, F66 transgenic mice exhibit dramatic increases in skeletal muscle mass throughout the body. We examined the effect of crossing the F66 transgene into Dysf−/− mice. At early ages, F66 transgene expression in Dysf−/− mice (i.e. F66;Dysf−/− mice) caused increased muscle mass to a similar extent as F66 did in a wild-type (wt) background (Fig. 1A–D; Supplementary Material, Table S1). Hence, blockade of the myostatin signaling pathway by Fst is capable of inducing muscle hypertrophy in the absence of functional dysferlin. These early gains in muscle weights, however, were not maintained as the mice aged, with muscle masses in F66;Dysf−/− mice decreasing sharply beginning at ∼4 months of age; in fact, by 8 months of age, F66;Dysf−/− mice showed even lower muscle weights than Dysf−/− mice.Figure 1.


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)

Hypertrophy induced by Fst transgene expression accelerates muscular degeneration in Dysf−/− mice. (A–D) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in Dysf−/− mice as a function of age. Graphs were made from the data shown in Supplementary Material, Table S1. Note the dramatic loss of muscle mass induced by F66 in Dysf−/− mice beginning at 4 months of age. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.05 versus Dysf−/−; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (E–H) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in mdx mice as a function of age. Note that F66 did not induce muscle loss in mdx mice. Graphs were made from the data shown in Supplementary Material, Table S2. **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus mdx; ###P < 0.001 versus mdx; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (I) Sections were stained with H&E, von Kossa (to highlight calcified fibers) and Masson's trichrome (to highlight areas of fibrosis). The F66;Dysf−/− mice showed the pathologic changes including fibrosis and centrally nucleated muscle fibers, even at 10 weeks of age, when Dysf−/− mice showed no distinct muscular degeneration. The F66;mdx mice showed the pathologic changes similar to mdx mice. Scale bar represents 50 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581601&req=5

DDV288F1: Hypertrophy induced by Fst transgene expression accelerates muscular degeneration in Dysf−/− mice. (A–D) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in Dysf−/− mice as a function of age. Graphs were made from the data shown in Supplementary Material, Table S1. Note the dramatic loss of muscle mass induced by F66 in Dysf−/− mice beginning at 4 months of age. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.05 versus Dysf−/−; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (E–H) Effect of F66 on weights of pectoralis, triceps, quadriceps and gastrocnemius muscles in mdx mice as a function of age. Note that F66 did not induce muscle loss in mdx mice. Graphs were made from the data shown in Supplementary Material, Table S2. **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus mdx; ###P < 0.001 versus mdx; †P < 0.05 versus F66; ††P < 0.01 versus F66; †††P < 0.001 versus F66. (I) Sections were stained with H&E, von Kossa (to highlight calcified fibers) and Masson's trichrome (to highlight areas of fibrosis). The F66;Dysf−/− mice showed the pathologic changes including fibrosis and centrally nucleated muscle fibers, even at 10 weeks of age, when Dysf−/− mice showed no distinct muscular degeneration. The F66;mdx mice showed the pathologic changes similar to mdx mice. Scale bar represents 50 µm.
Mentions: To investigate the effect of blocking myostatin signaling in the setting of dysferlinopathy, we used both genetic and pharmacological approaches in mice. For the genetic approach, we overexpressed follistatin (Fst), which is a secreted protein capable of binding and inhibiting various members of the TGF-β superfamily, including myostatin (20). For these studies, we utilized a transgenic mouse line (F66) in which we had expressed Fst under the control of a skeletal muscle-specific myosin light chain promoter/enhancer (20). As shown in Figure 1A–D and Supplementary Material, Table S1, and as we reported previously, F66 transgenic mice exhibit dramatic increases in skeletal muscle mass throughout the body. We examined the effect of crossing the F66 transgene into Dysf−/− mice. At early ages, F66 transgene expression in Dysf−/− mice (i.e. F66;Dysf−/− mice) caused increased muscle mass to a similar extent as F66 did in a wild-type (wt) background (Fig. 1A–D; Supplementary Material, Table S1). Hence, blockade of the myostatin signaling pathway by Fst is capable of inducing muscle hypertrophy in the absence of functional dysferlin. These early gains in muscle weights, however, were not maintained as the mice aged, with muscle masses in F66;Dysf−/− mice decreasing sharply beginning at ∼4 months of age; in fact, by 8 months of age, F66;Dysf−/− mice showed even lower muscle weights than Dysf−/− mice.Figure 1.

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