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.One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression.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 ACVR2B/Fc administration on muscle weights, muscle histopathology and serum CK levels in Dysf−/− mice. (A) Effect of ACVR2B/Fc on muscle weights. Bars indicate percent increase in muscle weights in ACVR2B/Fc-injected wt and Dysf−/− mice compared with PBS-injected wt and Dysf−/− mice, respectively. ACVR2B/Fc and PBS were administered by weekly i.p. injections over a span of 4 weeks at 10 mg kg−1 starting at age 6 weeks and 7 months. All calculations were made from the data shown in Supplementary Material, Table S6. (B) Sections of the quadriceps muscles stained with H&E and Masson's trichrome. Note that ACVR2B/Fc-injected Dysf−/− mice showed significant increases in muscle fiber diameters comparable to ACVR2B/Fc-injected wt mice and decreases in the extent of fibrosis compared with the PBS-injected Dysf−/− mice even at age 8 months. Scale bar represents 50 µm. (C) Electron microscope images. Note the membrane-bound spaces surrounded by swollen mitochondria in Dysf−/− myofiber (arrows). No specific changes were found in ACVR2B/Fc-injected wt muscles. However, ACVR2B/Fc-injected Dysf−/− myofiber showed reduction of membrane-bound spaces and swollen mitochondria compared with Dysf−/− myofiber. Scale bar represents 1 µm. (D) Effect of ACVR2B/Fc on serum CK levels. Note the increases in serum CK levels in ACVR2B/Fc-injected Dysf−/− mice compared with PBS-injected Dysf−/− mice at both 10 weeks and 8 months of age (P < 0.01). The graph was made from the data shown in Supplementary Material, Table S7.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV288F3: Effect of ACVR2B/Fc administration on muscle weights, muscle histopathology and serum CK levels in Dysf−/− mice. (A) Effect of ACVR2B/Fc on muscle weights. Bars indicate percent increase in muscle weights in ACVR2B/Fc-injected wt and Dysf−/− mice compared with PBS-injected wt and Dysf−/− mice, respectively. ACVR2B/Fc and PBS were administered by weekly i.p. injections over a span of 4 weeks at 10 mg kg−1 starting at age 6 weeks and 7 months. All calculations were made from the data shown in Supplementary Material, Table S6. (B) Sections of the quadriceps muscles stained with H&E and Masson's trichrome. Note that ACVR2B/Fc-injected Dysf−/− mice showed significant increases in muscle fiber diameters comparable to ACVR2B/Fc-injected wt mice and decreases in the extent of fibrosis compared with the PBS-injected Dysf−/− mice even at age 8 months. Scale bar represents 50 µm. (C) Electron microscope images. Note the membrane-bound spaces surrounded by swollen mitochondria in Dysf−/− myofiber (arrows). No specific changes were found in ACVR2B/Fc-injected wt muscles. However, ACVR2B/Fc-injected Dysf−/− myofiber showed reduction of membrane-bound spaces and swollen mitochondria compared with Dysf−/− myofiber. Scale bar represents 1 µm. (D) Effect of ACVR2B/Fc on serum CK levels. Note the increases in serum CK levels in ACVR2B/Fc-injected Dysf−/− mice compared with PBS-injected Dysf−/− mice at both 10 weeks and 8 months of age (P < 0.01). The graph was made from the data shown in Supplementary Material, Table S7.

Mentions: As a complementary approach to these genetic studies, we also examined the effect of blocking myostatin signaling pharmacologically by direct administration of a myostatin inhibitor to Dysf−/− mice. We showed previously that myostatin is capable of binding the two activin type II receptors, ACVR2 and ACVR2B (20), and that a soluble form of ACVR2B in which the extracellular domain of the receptor is fused to an Fc domain can cause significant muscle hypertrophy when given systemically to wt mice (24). We examined the effect of administering this soluble receptor (ACVR2B/Fc) to Dysf−/− mice. As shown in Figure 3A and Supplementary Material, Table S6, Dysf−/− mice given four weekly intraperitoneal (i.p.) injections of ACVR2B/Fc beginning at either 6 weeks or 7 months of age showed significant increases in muscle mass comparable to wt mice injected with ACVR2B/Fc. Moreover, fibrotic changes seen in 8-month-old Dysf−/− mice appeared to be significantly ameliorated by ACVR2B/Fc treatment (Fig. 3B); these histological improvements were consistent with what had been reported for ACVR2B/Fc treatment of mdx mice (18). EM analysis also showed that membrane-bound spaces surrounded by swollen mitochondria normally seen in Dysf−/− myofibers were less prominent in muscles of ACVR2B/Fc-treated Dysf−/− mice (Fig. 3C). Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf−/− mice at both 10 weeks and 8 months of age (Fig. 3D; Supplementary Material, Table S7), suggesting that hypertrophy induced by ACVR2B/Fc administration to Dysf−/− mice may have some adverse effects as well, though not nearly to the degree seen with Fst overexpression.Figure 3.


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 ACVR2B/Fc administration on muscle weights, muscle histopathology and serum CK levels in Dysf−/− mice. (A) Effect of ACVR2B/Fc on muscle weights. Bars indicate percent increase in muscle weights in ACVR2B/Fc-injected wt and Dysf−/− mice compared with PBS-injected wt and Dysf−/− mice, respectively. ACVR2B/Fc and PBS were administered by weekly i.p. injections over a span of 4 weeks at 10 mg kg−1 starting at age 6 weeks and 7 months. All calculations were made from the data shown in Supplementary Material, Table S6. (B) Sections of the quadriceps muscles stained with H&E and Masson's trichrome. Note that ACVR2B/Fc-injected Dysf−/− mice showed significant increases in muscle fiber diameters comparable to ACVR2B/Fc-injected wt mice and decreases in the extent of fibrosis compared with the PBS-injected Dysf−/− mice even at age 8 months. Scale bar represents 50 µm. (C) Electron microscope images. Note the membrane-bound spaces surrounded by swollen mitochondria in Dysf−/− myofiber (arrows). No specific changes were found in ACVR2B/Fc-injected wt muscles. However, ACVR2B/Fc-injected Dysf−/− myofiber showed reduction of membrane-bound spaces and swollen mitochondria compared with Dysf−/− myofiber. Scale bar represents 1 µm. (D) Effect of ACVR2B/Fc on serum CK levels. Note the increases in serum CK levels in ACVR2B/Fc-injected Dysf−/− mice compared with PBS-injected Dysf−/− mice at both 10 weeks and 8 months of age (P < 0.01). The graph was made from the data shown in Supplementary Material, Table S7.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV288F3: Effect of ACVR2B/Fc administration on muscle weights, muscle histopathology and serum CK levels in Dysf−/− mice. (A) Effect of ACVR2B/Fc on muscle weights. Bars indicate percent increase in muscle weights in ACVR2B/Fc-injected wt and Dysf−/− mice compared with PBS-injected wt and Dysf−/− mice, respectively. ACVR2B/Fc and PBS were administered by weekly i.p. injections over a span of 4 weeks at 10 mg kg−1 starting at age 6 weeks and 7 months. All calculations were made from the data shown in Supplementary Material, Table S6. (B) Sections of the quadriceps muscles stained with H&E and Masson's trichrome. Note that ACVR2B/Fc-injected Dysf−/− mice showed significant increases in muscle fiber diameters comparable to ACVR2B/Fc-injected wt mice and decreases in the extent of fibrosis compared with the PBS-injected Dysf−/− mice even at age 8 months. Scale bar represents 50 µm. (C) Electron microscope images. Note the membrane-bound spaces surrounded by swollen mitochondria in Dysf−/− myofiber (arrows). No specific changes were found in ACVR2B/Fc-injected wt muscles. However, ACVR2B/Fc-injected Dysf−/− myofiber showed reduction of membrane-bound spaces and swollen mitochondria compared with Dysf−/− myofiber. Scale bar represents 1 µm. (D) Effect of ACVR2B/Fc on serum CK levels. Note the increases in serum CK levels in ACVR2B/Fc-injected Dysf−/− mice compared with PBS-injected Dysf−/− mice at both 10 weeks and 8 months of age (P < 0.01). The graph was made from the data shown in Supplementary Material, Table S7.
Mentions: As a complementary approach to these genetic studies, we also examined the effect of blocking myostatin signaling pharmacologically by direct administration of a myostatin inhibitor to Dysf−/− mice. We showed previously that myostatin is capable of binding the two activin type II receptors, ACVR2 and ACVR2B (20), and that a soluble form of ACVR2B in which the extracellular domain of the receptor is fused to an Fc domain can cause significant muscle hypertrophy when given systemically to wt mice (24). We examined the effect of administering this soluble receptor (ACVR2B/Fc) to Dysf−/− mice. As shown in Figure 3A and Supplementary Material, Table S6, Dysf−/− mice given four weekly intraperitoneal (i.p.) injections of ACVR2B/Fc beginning at either 6 weeks or 7 months of age showed significant increases in muscle mass comparable to wt mice injected with ACVR2B/Fc. Moreover, fibrotic changes seen in 8-month-old Dysf−/− mice appeared to be significantly ameliorated by ACVR2B/Fc treatment (Fig. 3B); these histological improvements were consistent with what had been reported for ACVR2B/Fc treatment of mdx mice (18). EM analysis also showed that membrane-bound spaces surrounded by swollen mitochondria normally seen in Dysf−/− myofibers were less prominent in muscles of ACVR2B/Fc-treated Dysf−/− mice (Fig. 3C). Despite these potentially beneficial effects, ACVR2B/Fc treatment caused increases in serum CK levels in some Dysf−/− mice at both 10 weeks and 8 months of age (Fig. 3D; Supplementary Material, Table S7), suggesting that hypertrophy induced by ACVR2B/Fc administration to Dysf−/− mice may have some adverse effects as well, though not nearly to the degree seen with Fst overexpression.Figure 3.

Bottom Line: As a result, there is extensive effort directed at developing drugs capable of targeting myostatin to treat patients with muscle loss.One potential concern with this therapeutic approach in patients with muscle degenerative diseases like muscular dystrophy is that inducing hypertrophy may increase stress on dystrophic fibers, thereby accelerating disease progression.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