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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

Effect of Fst transgene expression on muscle fiber integrity and function in Dysf−/− mice. (A) Electron microscope images of quadriceps muscles at 10 weeks of age. While wt mice showed the regular sarcomeric pattern with no degenerative change in mitochondrial morphology, Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria (arrows in Dysf−/− image). F66 muscles showed randomly fragmented myofibrils in regular sarcomeric pattern, representing Type IIb fast-twitch fibers. F66;Dysf−/− muscles showed accumulation of vacuoles and mitochondria aggregation in subsarcolemmal area, necrotic fiber with complete loss of myofibrils (arrow in F66;Dysf−/− image) and fibroblast next to necrotic fiber (arrowhead). Scale bar represents 2 µm. (B) Serum CK (U/L) levels as a function of age. Note the sharp increase in CK levels in F66;Dysf−/− mice at 10 weeks of age. Graphs were made from the data shown in Supplementary Material, Table S3. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.01 versus Dysf−/−; ##P < 0.001 versus Dysf−/−. (C) EBD uptake by abdominal, quadriceps, gastrocnemius/soleus, gluteus/hamstring and triceps muscles. Note the increased EBD uptake in F66;Dysf−/− mice compared with the other groups. Graphs were made from the data shown in Supplementary Material, Table S5. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−. (D) Specific force of EDL muscles from wt, Dysf−/−, F66 and F66;Dysf−/− mice at 4 months of age. F66;Dysf−/− mice showed a significant decrease in specific force compared with others. *P < 0.05 versus wt; **P < 0.01 versus wt; #P < 0.05 versus Dysf−/−; †P < 0.05 versus F66.
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DDV288F2: Effect of Fst transgene expression on muscle fiber integrity and function in Dysf−/− mice. (A) Electron microscope images of quadriceps muscles at 10 weeks of age. While wt mice showed the regular sarcomeric pattern with no degenerative change in mitochondrial morphology, Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria (arrows in Dysf−/− image). F66 muscles showed randomly fragmented myofibrils in regular sarcomeric pattern, representing Type IIb fast-twitch fibers. F66;Dysf−/− muscles showed accumulation of vacuoles and mitochondria aggregation in subsarcolemmal area, necrotic fiber with complete loss of myofibrils (arrow in F66;Dysf−/− image) and fibroblast next to necrotic fiber (arrowhead). Scale bar represents 2 µm. (B) Serum CK (U/L) levels as a function of age. Note the sharp increase in CK levels in F66;Dysf−/− mice at 10 weeks of age. Graphs were made from the data shown in Supplementary Material, Table S3. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.01 versus Dysf−/−; ##P < 0.001 versus Dysf−/−. (C) EBD uptake by abdominal, quadriceps, gastrocnemius/soleus, gluteus/hamstring and triceps muscles. Note the increased EBD uptake in F66;Dysf−/− mice compared with the other groups. Graphs were made from the data shown in Supplementary Material, Table S5. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−. (D) Specific force of EDL muscles from wt, Dysf−/−, F66 and F66;Dysf−/− mice at 4 months of age. F66;Dysf−/− mice showed a significant decrease in specific force compared with others. *P < 0.05 versus wt; **P < 0.01 versus wt; #P < 0.05 versus Dysf−/−; †P < 0.05 versus F66.

Mentions: We also examined the muscles in F66;Dysf−/− mice by electron microscopy (EM). As shown in Figure 2A, EM analysis of quadriceps muscles of Dysf−/− mice at 10 weeks of age generally showed regular cross-striations with well-arranged myofibrils, although some fibers in Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria, and inflammatory cell infiltration between fibers was also seen. In F66;Dysf−/− mice, however, in addition to the inflammatory cell infiltration, mitochondrial degeneration was more prominent and severe, and necrotic fibers surrounded by fibroblasts were more frequently observed. These changes were not observed in F66 muscles, which showed regular cross-striations with little evidence of muscle fiber degeneration, although we did observe occasional fibers in F66 mice with randomly fragmented myofibrils.Figure 2.


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)

Effect of Fst transgene expression on muscle fiber integrity and function in Dysf−/− mice. (A) Electron microscope images of quadriceps muscles at 10 weeks of age. While wt mice showed the regular sarcomeric pattern with no degenerative change in mitochondrial morphology, Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria (arrows in Dysf−/− image). F66 muscles showed randomly fragmented myofibrils in regular sarcomeric pattern, representing Type IIb fast-twitch fibers. F66;Dysf−/− muscles showed accumulation of vacuoles and mitochondria aggregation in subsarcolemmal area, necrotic fiber with complete loss of myofibrils (arrow in F66;Dysf−/− image) and fibroblast next to necrotic fiber (arrowhead). Scale bar represents 2 µm. (B) Serum CK (U/L) levels as a function of age. Note the sharp increase in CK levels in F66;Dysf−/− mice at 10 weeks of age. Graphs were made from the data shown in Supplementary Material, Table S3. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.01 versus Dysf−/−; ##P < 0.001 versus Dysf−/−. (C) EBD uptake by abdominal, quadriceps, gastrocnemius/soleus, gluteus/hamstring and triceps muscles. Note the increased EBD uptake in F66;Dysf−/− mice compared with the other groups. Graphs were made from the data shown in Supplementary Material, Table S5. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−. (D) Specific force of EDL muscles from wt, Dysf−/−, F66 and F66;Dysf−/− mice at 4 months of age. F66;Dysf−/− mice showed a significant decrease in specific force compared with others. *P < 0.05 versus wt; **P < 0.01 versus wt; #P < 0.05 versus Dysf−/−; †P < 0.05 versus F66.
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DDV288F2: Effect of Fst transgene expression on muscle fiber integrity and function in Dysf−/− mice. (A) Electron microscope images of quadriceps muscles at 10 weeks of age. While wt mice showed the regular sarcomeric pattern with no degenerative change in mitochondrial morphology, Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria (arrows in Dysf−/− image). F66 muscles showed randomly fragmented myofibrils in regular sarcomeric pattern, representing Type IIb fast-twitch fibers. F66;Dysf−/− muscles showed accumulation of vacuoles and mitochondria aggregation in subsarcolemmal area, necrotic fiber with complete loss of myofibrils (arrow in F66;Dysf−/− image) and fibroblast next to necrotic fiber (arrowhead). Scale bar represents 2 µm. (B) Serum CK (U/L) levels as a function of age. Note the sharp increase in CK levels in F66;Dysf−/− mice at 10 weeks of age. Graphs were made from the data shown in Supplementary Material, Table S3. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; #P < 0.01 versus Dysf−/−; ##P < 0.001 versus Dysf−/−. (C) EBD uptake by abdominal, quadriceps, gastrocnemius/soleus, gluteus/hamstring and triceps muscles. Note the increased EBD uptake in F66;Dysf−/− mice compared with the other groups. Graphs were made from the data shown in Supplementary Material, Table S5. *P < 0.05 versus wt; **P < 0.01 versus wt; ***P < 0.001 versus wt; ##P < 0.01 versus Dysf−/−; ###P < 0.001 versus Dysf−/−. (D) Specific force of EDL muscles from wt, Dysf−/−, F66 and F66;Dysf−/− mice at 4 months of age. F66;Dysf−/− mice showed a significant decrease in specific force compared with others. *P < 0.05 versus wt; **P < 0.01 versus wt; #P < 0.05 versus Dysf−/−; †P < 0.05 versus F66.
Mentions: We also examined the muscles in F66;Dysf−/− mice by electron microscopy (EM). As shown in Figure 2A, EM analysis of quadriceps muscles of Dysf−/− mice at 10 weeks of age generally showed regular cross-striations with well-arranged myofibrils, although some fibers in Dysf−/− mice showed membrane-bound spaces surrounded by swollen mitochondria, and inflammatory cell infiltration between fibers was also seen. In F66;Dysf−/− mice, however, in addition to the inflammatory cell infiltration, mitochondrial degeneration was more prominent and severe, and necrotic fibers surrounded by fibroblasts were more frequently observed. These changes were not observed in F66 muscles, which showed regular cross-striations with little evidence of muscle fiber degeneration, although we did observe occasional fibers in F66 mice with randomly fragmented myofibrils.Figure 2.

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