Myostatin Blockade: A New Way to Enhance Skeletal Muscle Repair in Old Age?
Authors: Zipora Yablonka-Reuveni
Journal: Molecular Therapy (2007)

Age-related muscle deterioration, called sarcopenia, is characterized by a decline in skeletal muscle mass, strength, and endurance. Sarcopenia is a major health issue in aging humans, because it reduces their capacity to carry out basic activities of daily life and puts the elderly at increased risk of injury.1Karakelides H Sreekumaran Nair K Sarcopenia of aging and its metabolic impact.Curr Top Dev Biol. 2005; 68: 123-148Crossref PubMed Scopus (201) Google Scholar Repair of myofibers, the functional blocks of skeletal muscle, is made possible by satellite cells, myogenic stem cells residing beneath the myofiber basal lamina.2Zammit PS Partridge TA Yablonka-Reuveni Z The skeletal muscle satellite cell: the stem cell that came in from the cold.J Histochem Cytochem. 2006; 54: 1177-1191Crossref PubMed Scopus (492) Google Scholar Even without overt muscle trauma, subtle muscle injuries that take place during routine activity raise a continuous demand for myofiber repair throughout life. Although functional satellite cells are present in the muscle throughout life, their performance in vivo is impaired in old age.3Conboy IM Conboy MJ Wagers AJ Girma ER Weissman IL Rando TA Rejuvenation of aged progenitor cells by exposure to a young systemic environment.Nature. 2005; 433: 760-764Crossref PubMed Scopus (1590) Google Scholar,4Shefer G Van de Mark DP Richardson JB Yablonka-Reuveni Z Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle.Dev Biol. 2006; 294: 50-66Crossref PubMed Scopus (336) Google Scholar This decline in myogenic stem cell function is potentially contributory to the development of sarcopenia. In a new study in this issue of Molecular Therapy, Siriett et al. report that a short-term blockade of myostatin, a member of the transforming growth factor-β superfamily, enhances muscle regeneration during sarcopenia in a mouse model.5Siriett V Salerno MS Berry C Nicholas G Bower R Kambadur R et al.Antagonism of myostatin enhances muscle regeneration during sarcopenia.Mol Ther. 2007; 15: 1463-1470Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar On the basis of their findings the authors propose that the antagonism of myostatin has significant therapeutic potential in the alleviation of sarcopenia. Myostatin, a negative regulator of skeletal muscle growth, contributes to the maintenance of appropriate muscle mass during development and in adult life. Loss of myostatin activity in cattle, mice, and humans leads to profound muscle overgrowth, associated with increased size and number of fibers.6Lee SJ McPherron AC Regulation of myostatin activity and muscle growth.Proc Natl Acad Sci USA. 2001; 98: 9306-9311Crossref PubMed Scopus (1234) Google Scholar,7McPherron AC Lee SJ Double muscling in cattle due to mutations in the myostatin gene.Proc Natl Acad Sci USA. 1997; 94: 12457-12461Crossref PubMed Scopus (1548) Google Scholar,8McPherron AC Lawler AM Lee SJ Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member.Nature. 1997; 387: 83-90Crossref PubMed Scopus (3066) Google Scholar,9Schuelke M Wagner KR Stolz LE Hubner C Riebel T Komen W et al.Myostatin mutation associated with gross muscle hypertrophy in a child.N Engl J Med. 2004; 350: 2682-2688Crossref PubMed Scopus (1060) Google Scholar Constitutive absence of myostatin function, such as in myostatin-null animals, does not permit evaluation of the role of myostatin in adult life, because the observed increased muscle mass can be a consequence of events taking place during muscle histogenesis or prenatal development. Nevertheless, a conditional gene targeting approach exploiting the Cre-lox system demonstrated that postnatal inactivation of the myostatin gene is sufficient to cause a generalized muscular hypertrophy of the same magnitude as that observed in myostatin-knockout mice.10Welle S Bhatt K Pinkert CA Tawil R Thornton CA Muscle growth after postdevelopmental myostatin gene knockout.Am J Physiol Endocrinol Metab. 2007; 292: E985-E991Crossref PubMed Scopus (76) Google Scholar Conversely, systemic expression of myostatin leads to reduced muscle mass and muscle wasting (cachexia).11Zimmers TA Davies MV Koniaris LG Haynes P Esquela AF Tomkinson KN et al.Induction of cachexia in mice by systemically administered myostatin.Science. 2002; 296: 1486-1488Crossref PubMed Scopus (729) Google Scholar Ablation of myostatin function by genetic manipulation or myostatin blockade has also been shown to ameliorate the dystrophic phenotype of certain myopathies. In the mdx mouse model of Duchenne muscular dystrophy, deletion of the myostatin gene or blocking myostatin function enhanced muscle mass and reduced disease severity.12Wagner KR McPherron AC Winik N Lee SJ Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.Ann Neurol. 2002; 52: 832-836Crossref PubMed Scopus (318) Google Scholar,13Bogdanovich S Krag TOB Barton ER Morris LD Whittemore LA Ahima RS et al.Functional improvement of dystrophic muscle by myostatin blockade.Nature. 2002; 420: 418-421Crossref PubMed Scopus (699) Google Scholar In contrast, loss of myostatin activity in the dyW/dyW mouse model of laminin-deficient congenital muscular dystrophy, a more severe and lethal disease model, did not improve all aspects of muscle pathology.14Li ZF Shelton GD Engvall E Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality.Am J Pathol. 2005; 166: 491-497Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Genetic manipulation or antibody-mediated inhibition of myostatin function in a model of limb-girdle muscular dystrophy (mice lacking δ-sarcoglycan) improved muscle mass and regeneration and reduced fibrosis. However, this improvement was achieved only during the phase of postnatal growth but not in adults.15Parsons SA Millay DP Sargent MA McNally EM Molkentin JD Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy.Am J Pathol. 2006; 168: 1975-1985Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Collectively, the aforementioned in vivo studies suggest that myostatin inhibition may benefit muscle function in certain dystrophic and atrophic conditions. In the study reported in this issue, Sirriet et al. describe the development of a truncated form of myostatin, which they used as an antagonist for blocking myostatin in old mice, and this resulted in more efficient muscle regeneration. Myostatin is proteolytically processed at amino acid 266, giving rise to a biologically active mature myostatin spanning amino acids 266–375 (ref. 8McPherron AC Lawler AM Lee SJ Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member.Nature. 1997; 387: 83-90Crossref PubMed Scopus (3066) Google Scholar). This 110–amino acid protein binds to the activin type IIB receptor as a dimer to transduce its signal.6Lee SJ McPherron AC Regulation of myostatin activity and muscle growth.Proc Natl Acad Sci USA. 2001; 98: 9306-9311Crossref PubMed Scopus (1234) Google Scholar To antagonize myostatin, the authors produced a C-terminal truncation, spanning amino acids 266–350, as a dominant negative (mimetic) protein. This C-terminal truncated form was expressed in an Escherichia coliexpression system and purified to homogeneity for further in vivo and cell culture studies using a mouse model. Injection of the antagonist to notexin (snake venom)-injured muscle of mice resulted in earlier formation of nascent myofibers, an associated decline in necrotic areas, and increased myofiber diameter as compared with saline-treated muscle. Furthermore, antagonist-treated muscle displayed reduced levels of collagen deposits, which typically develop following notexin injury. As shown by the authors, expression levels of characteristic proteins that mark satellite cells and their proliferating progeny—i.e., Pax7 and MyoD (ref. 4Shefer G Van de Mark DP Richardson JB Yablonka-Reuveni Z Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle.Dev Biol. 2006; 294: 50-66Crossref PubMed Scopus (336) Google Scholar)—were also elevated, and the enhanced proliferative activity of satellite cells in response to the antagonist was also demonstrated in isolated myofiber cultures. Importantly, the antagonist impaired the negative effect of myostatin on macrophage migration into the injured muscle site and increased migration of myoblasts and macrophages in chemotaxis assays of primary cells isolated from 2-year-old mice. In sum, the authors established that their myostatin antagonist led to satellite cell activation, increased expression of myogenic cell markers, and greater myoblast and macrophage cell migration, contributing collectively to enhanced muscle regeneration after induced injury in aged mice. Importantly, the antagonist demonstrated a high degree of efficacy, in that only minimal doses during the critical period of regeneration after injury were sufficient to restore the myogenic and inflammatory responses in the aged environment. The present report corroborates earlier studies by the authors and independent studies by Wagner and colleagues, showing that old myostatin-null mice continue to display healthier muscle with increased mass and strength relative to controls. Furthermore, muscles of myostatin-null mice from adult and aging mice regenerated robustly from both chronic and acute injury and showed reduced fibrosis.16McCroskery S Thomas M Platt L Hennebry A Nishimura T McLeay L et al.Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice.J Cell Sci. 2005; 118: 3531-3541Crossref PubMed Scopus (159) Google Scholar,17Siriett V Platt L Salerno MS Ling N Kambadur R Sharma M Prolonged absence of myostatin reduces sarcopenia.J Cell Physiol. 2006; 209: 866-873Crossref PubMed Scopus (117) Google Scholar,18Wagner KR Liu X Chang X Allen RE Muscle regeneration in the prolonged absence of myostatin.Proc Natl Acad Sci USA. 2005; 102: 2519-2524Crossref PubMed Scopus (163) Google Scholar In view of their new findings, Siriett et al. propose that the antagonism of myostatin has significant therapeutic potential in the alleviation of sarcopenia. The means by which myostatin regulates muscle mass has remained unknown. From an evolutionary point of view, it is hard to envision that myostatin is bad for muscle. On the contrary, it may repress satellite cell proliferation so as to maintain sufficient progenitors for future recruitment when needed. Yet, following muscle trauma, a rapid recruitment of myogenic cells is needed but does not happen in the aging muscle, probably as a result of a lack of proper signaling agents in the surrounding niche.3Conboy IM Conboy MJ Wagers AJ Girma ER Weissman IL Rando TA Rejuvenation of aged progenitor cells by exposure to a young systemic environment.Nature. 2005; 433: 760-764Crossref PubMed Scopus (1590) Google Scholar Hence, short-term blockade of myostatin function may support better healing of aged muscle by facilitating enhanced recruitment of satellite cells and other necessary inflammatory cells in the aging environment. Unlike the localized-injury model used in the present study, the application of myostatin blockade therapy as a means to combat sarcopenia presents a considerable challenge, considering that sarcopenia is a developmental process that progresses gradually throughout life.1Karakelides H Sreekumaran Nair K Sarcopenia of aging and its metabolic impact.Curr Top Dev Biol. 2005; 68: 123-148Crossref PubMed Scopus (201) Google Scholar Thus, future studies will need to address both the time at which the therapy is initiated and the means to distribute the therapeutic agent throughout the body. Moreover, as is the case for pharmacological agents introduced to combat osteoporosis, the road to a safe systemic drug is not necessarily going to be simple. Nevertheless, a similar strategy to that discussed by Siriett et al. might be applicable in the near future for enhancing regeneration of injured muscle following localized muscle trauma. This approach may prove useful not only for the mitigation of muscle wasting in the elderly population but also for accelerating muscle regeneration in younger individuals inflicted by severe wound trauma. This work was supported by the National Institute on Aging (AG021566 and AG013798).