Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice

Abstract

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1δ4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. X-linked myotubular myopathy (XLMTM) is a severe form of congenital myopathy with an estimated incidence of 1:50,000 male births that most often presents with severe perinatal weakness and respiratory failure.1Heckmatt J.Z. Sewry C.A. Hodes D. Dubowitz V. Congenital centronuclear (myotubular) myopathy. A clinical, pathological and genetic study in eight children.Brain. 1985; 108: 941-964Crossref PubMed Scopus (91) Google Scholar, 2Jungbluth H. Wallgren-Pettersson C. Laporte J. Centronuclear (myotubular) myopathy.Orphanet J Rare Dis. 2008; 3: 26Crossref PubMed Scopus (237) Google Scholar Many patients with XLMTM die within the first year of life despite the use of mechanical ventilation, and no treatments approved by the Food and Drug Administration are available. XLMTM is caused by mutations in the gene that encodes myotubularin (MTM1), which is a phosphoinositide phosphatase thought to be involved in endosomal trafficking, cytoskeletal organization, apoptosis, and/or maintenance of the sarcoplasmic reticulum/T-tubular system within myofibers.3Buj-Bello A. Fougerousse F. Schwab Y. Messaddeq N. Spehner D. Pierson C.R. Durand M. Kretz C. Danos O. Douar A.M. Beggs A.H. Schultz P. Montus M. Denefle P. Mandel J.L. 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Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.Am J Pathol. 2012; 181: 961-968Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Muscle biopsies from patients with XLMTM display excessively small fibers with increased numbers of fibers that contain central nuclei and central aggregation of organelles.9Pierson C.R. Tomczak K. Agrawal P. Moghadaszadeh B. Beggs A.H. X-linked myotubular and centronuclear myopathies.J Neuropathol Exp Neurol. 2005; 64: 555-564Crossref PubMed Scopus (84) Google Scholar Although the number of centrally nucleated fibers bears little relationship to a patient's prognosis, there is a clear correlation between the degree of fiber smallness at birth and the severity of the patients' C.R. Agrawal J. Beggs A.H. with type and in X-linked myotubular 17: Full Text Full Text PDF PubMed Scopus Google Scholar murine of myotubularin deficiency are the severely symptomatic Mtm1δ4 to Mtm1 in A. Fougerousse F. Schwab Y. Messaddeq N. Spehner D. Pierson C.R. Durand M. Kretz C. Danos O. Douar A.M. Beggs A.H. Schultz P. Montus M. Denefle P. Mandel J.L. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis.Hum Mol Genet. 2008; 17: 2132-2143Crossref PubMed Scopus (101) Google Scholar, L. N. A. C. Messaddeq N. Kretz C. D. Beggs A.H. B. Mandel J.L. Laporte J. V. Buj-Bello A. T-tubule disorganization and in muscle fibers myotubularin lipid A. 2009; PubMed Scopus Google Scholar, M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google and the symptomatic Mtm1 p.R69C C.R. N. M.W. Buj-Bello A. J.J. Beggs A.H. the human p.R69C in murine Mtm1 results in and a less severe myotubular myopathy Mol Genet. 2012; PubMed Scopus Google Scholar of which display weakness and smallness and similar to that in of the relationship between and symptomatic severity in patients with XLMTM and in Mtm1δ4 that of smallness in myotubularin deficiency of or of the activin type IIB receptor be to of to to the to the growth which the cell and several to M. L. M. R. satellite cell and PubMed Scopus Google Scholar, D. of muscle PubMed Scopus Google Scholar We recently reported a of in Mtm1δ4 which produced of life with increases in and hypertrophy to type 2b myofibers in Mtm1δ4 M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar hypertrophy in muscle fiber in wild-type M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. M.S. R. J.L. Administration of a activin type IIB receptor skeletal muscle growth of fiber PubMed Scopus Google Scholar which suggests that myotubularin deficiency with the of hypertrophic in We that the of the therapeutic observed in Mtm1δ4 have to the severity of the have now study in the less severely Mtm1 p.R69C C.R. N. M.W. Buj-Bello A. J.J. Beggs A.H. the human p.R69C in murine Mtm1 results in and a less severe myotubular myopathy Mol Genet. 2012; PubMed Scopus Google Scholar treatment of Mtm1 p.R69C not increases in or and treatment-induced hypertrophy was observed in the Mtm1 p.R69C gastrocnemius The ability of muscles to respond to treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. The between and muscles in Mtm1 p.R69C was to levels of phosphorylated ribosomal protein and levels of eukaryotic elongation factor 2 kinase in the gastrocnemius muscle that were not observed in Mtm1 p.R69C muscles or in and are of the growth and kinase that are involved in the of protein with a in the of cell that in O. of ribosomal protein of Mol 2008; PubMed Scopus Google Our findings indicate that the response to hypertrophic not with of hypertrophic the but by muscle type and fiber type and in XLMTM is by the of the Mtm1 results that there is not the of muscle and the of muscle and fiber in future of hypertrophic were performed with from the and at of and Mtm1 was performed M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, C.R. N. M.W. Buj-Bello A. J.J. Beggs A.H. the human p.R69C in murine Mtm1 results in and a less severe myotubular myopathy Mol Genet. 2012; PubMed Scopus Google Scholar, A. V. Messaddeq N. H. Laporte J. J.F. Mandel J.L. The lipid phosphatase myotubularin is skeletal muscle maintenance but not in A. PubMed Scopus (177) Google Scholar and Mtm1 p.R69C were with a at a of or an of with M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar from of life were at of a in therapeutic were the treatment strength was with the use of a by the a and to from the by The of with a between was animals were by the a the at a of and the of the to the that not within were The of with a between was were with by the of the and at were and of the from the and The and muscles were and in of or muscles were the of the muscle and with with the use of an with an and was of have M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar a that is of fiber The of human muscle biopsies with to fiber 19: PubMed Google Scholar fiber and the number of nucleated fibers were with of a of to to animals treatment fiber of quadriceps muscle were with and mouse type type or type 2b or and of in the number and type of fibers and in mouse was performed by the type 2b and type 2b a of quadriceps and gastrocnemius muscle from Mtm1 p.R69C and Mtm1 p.R69C was by a by that correlated with M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. 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Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.Am J Pathol. 2012; 181: 961-968Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar were by the number of within a and by the number of fibers to animals treatment Muscle from the and in the and from and Mtm1 p.R69C at or and Mtm1δ4 at of life were at the of and at muscles were in and with that inhibitor and phosphatase inhibitor were performed D. F. V. Wallgren-Pettersson C. 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R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar the present performed a similar the less severely symptomatic Mtm1 p.R69C mouse C.R. N. M.W. Buj-Bello A. J.J. Beggs A.H. the human p.R69C in murine Mtm1 results in and a less severe myotubular myopathy Mol Genet. 2012; PubMed Scopus Google Scholar to the of treatment in less severely symptomatic patients with that is less a treatment Mtm1 p.R69C than Mtm1δ4 and that treatment-induced hypertrophy was to muscles within Mtm1 p.R69C several factors that between have that the to respond to was associated with numbers of satellite in the abnormalities of hypertrophic in the Mtm1 p.R69C gastrocnemius muscle that were not present in the Mtm1 p.R69C quadriceps muscle or in levels of and levels of Although the relationship between of factors and treatment study several therapeutic and the of muscles and treatment are not A of that in several between treatment in Mtm1δ4 and Mtm1 p.R69C Mtm1δ4 and Mtm1 p.R69C in which is thought to be to the of myotubularin in Mtm1δ4 in with a small of myotubularin in Mtm1 p.R69C C.R. N. M.W. Buj-Bello A. J.J. Beggs A.H. the human p.R69C in murine Mtm1 results in and a less severe myotubular myopathy Mol Genet. 2012; PubMed Scopus Google Scholar Mtm1δ4 treatment produced increases in which to increases in the of muscles and M.W. R. N. Pierson C.R. A. Buj-Bello A. J.L. Beggs A.H. of activin receptor type increases strength and in J Pathol. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar to hypertrophy of a of and hypertrophy was to a of the the present of hypertrophy increased muscle and hypertrophy to the type 2b fiber were in the gastrocnemius muscles of Mtm1 p.R69C but were in the muscles and no were between the and muscles in that factor affect treatment that between muscles of the We to satellite cell and hypertrophic in the quadriceps and gastrocnemius muscles between muscles of the The of treatment to type 2b myofibers in study that Mtm1δ4 that the be involved in the of in the of in the of present have that of myotubularin results in of in and human skeletal muscle D. Myotubularin Biol 2011; PubMed Scopus Google Scholar and levels are reported to be increased that the is in L. Amoasii L. Kretz C. Messaddeq N. Mandel J.L. Laporte J. of myotubularin to muscle of the and J. PubMed Scopus Google Scholar the levels of were similar in with Mtm1 p.R69C and of from Mtm1δ4 and similar or increased levels of in Mtm1δ4 muscle indicate that the ability to is in mouse Although were to the of of the in was that the of was in with Mtm1 p.R69C but not Mtm1 p.R69C displayed increases in at and in response to treatment with with to hypertrophy reported the of the in hypertrophy by in C. A. hypertrophy J 2009; PubMed Scopus Google Scholar and mouse J.J. M. H. P. A. H. O. Muscle protein and are by of and J PubMed Scopus Google Scholar, O. H. P. B. L. M. The type growth factor receptor is the skeletal muscle 2012; PubMed Scopus Google Scholar, K. of skeletal muscle protein S6 kinase and ribosomal protein S6 by of in J 2009; PubMed Scopus Google Scholar the response to is not in A. J. deficiency muscle and function but not the response to 5: PubMed Scopus Google Scholar is not an hypertrophy in The abnormalities of hypertrophic in Mtm1 p.R69C were levels of and levels of in the gastrocnemius muscle in with the quadriceps muscle The of in the Mtm1 p.R69C gastrocnemius muscle is lower than that in muscles and muscles from Mtm1δ4 and at suggests that of the to protein in O. of ribosomal protein of Mol 2008; PubMed Scopus Google of and/or eukaryotic factor increases in protein of a in protein N. H. M. Y. P. O. protein S6 is a of cell and 2005; 19: PubMed Scopus Google Scholar and are thought to protein The relationship of and cell in the of the of the to associated with cell a of cell and muscle M. A. Y. A. N. E. J. O. in ribosomal protein S6 from muscle weakness that a growth and 2009; PubMed Scopus Google Scholar treatment in Mtm1 p.R69C not abnormalities that the of treatment in most but is that the levels of and the to with the treatment was in the gastrocnemius The between and and treatment in study are was not with the use of and higher levels in the Mtm1 p.R69C gastrocnemius muscle than the quadriceps muscle was not at higher levels in Although that muscles that hypertrophy in response to treatment higher satellite cell numbers than were in the satellite cell and hypertrophy have that satellite are not hypertrophy in the of S.M. N. C. of satellite myofibers in muscle hypertrophy by of the A. 2012; PubMed Scopus Google Scholar, muscle hypertrophy to satellite cell 2012; PubMed Scopus Google Scholar have satellite cell an of hypertrophy H. O. P. K. muscle hypertrophy satellite cell and of and J 2009; PubMed Scopus Google Scholar with the that affect satellite cell and to satellite cell in the of Y. L. of satellite cell PubMed Scopus Google Scholar muscle in J. of muscle in mouse model of type PubMed Scopus Google Scholar and satellite cell number in L. V. E. Hu Y. H. J. of and muscle in with J. 2011; PubMed Scopus Google Scholar the of present observed a relationship between treatment and satellite cell but the satellite to the hypertrophic response is less that the treatment from 2 of fibers are associated with satellite to the number of fibers associated with satellite to is not clear treatment produced satellite cell or the in satellite cell numbers that is observed with observed a similar of satellite in Mtm1 p.R69C muscles and Mtm1δ4 M.W. Alexander M.S. Viola M.G. Meng H. Joubert R. Gupta V. Motohashi N. Manfready R.A. Hsu C.P. Huang P. Buj-Bello A. Kunkel L.M. Beggs A.H. Gussoni E. Myotubularin-deficient myoblasts display increased apoptosis, delayed proliferation, and poor cell engraftment.Am J Pathol. 2012; 181: 961-968Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar and to an the Mtm1 p.R69C quadriceps and gastrocnemius muscles at that the of treatment was not a of satellite cell number between muscles in the the that the factors that are or of hypertrophy in the Mtm1 p.R69C quadriceps muscle satellite cell of satellite be a of treatment or with treatment in future that study that the treatment of be the of symptomatic severity and that the response to treatment between muscles from Mtm1 p.R69C Our findings indicate that a therapeutic in the treatment of myotubularin be in with A. Fougerousse F. Schwab Y. Messaddeq N. Spehner D. Pierson C.R. Durand M. Kretz C. Danos O. Douar A.M. Beggs A.H. Schultz P. Montus M. Denefle P. Mandel J.L. AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis.Hum Mol Genet. 2008; 17: 2132-2143Crossref PubMed Scopus (101) Google Scholar and M.W. D. Viola M.G. J.J. Meng H. Hsu C.P. M. Pierson C.R. Buj-Bello A. Beggs A.H. weakness and muscle in with X-linked myotubular Mol Genet. PubMed Scopus Google Scholar therapies XLMTM that are The muscle-specific of hypertrophy observed a the of treatment at the the hypertrophic are than the between of myotubularin muscle and fiber type to Although the the of treatment in Mtm1 p.R69C the and satellite cell numbers the of treatment in myotubularin deficiency or in We and Moghadaszadeh and and C. protein and with in and Mtm1δ4 at the of and in the quadriceps and gastrocnemius muscles of and Mtm1δ4 at is a and The numbers of to from the of the results in A. is to the The were from the in and the results were are