Author's personal copy Review Revisiting the paradigm of myostatin in vertebrates: Insights from fishes Jean-Charles Gabillard a,⇑ , Peggy R. Biga b , Pierre-Yves Rescan a , Iban Seiliez c a INRA, UR1037 Laboratoire de Physiologie et Génomique des Poissons, Equipe Croissance et Qualité de la Chair des Poissons, Campus de Beaulieu, 35000 Rennes, France b University of Alabama, Department of Biology, 1300 University Blvd, Campbell Hall 173, Birmingham, AL 35294, United States c INRA, UMR1067 Nutrition Métabolisme et Aquaculture, Pôle d’hydrobiologie, CD918, F-64310 St-Pée-sur-Nivelle, France article info Article history: Received 2 April 2013 Revised 9 August 2013 Accepted 15 August 2013 Available online 7 September 2013 Keywords: GDF8 Muscle growth Satellite cells Transgenesis TALEN Zing finger nuclease abstract In the last decade, myostatin (MSTN), a member of the TGFb superfamily, has emerged as a strong inhib- itor of muscle growth in mammals. In fish many studies reveal a strong conservation of mstn gene orga- nization, sequence, and protein structures. Because of ancient genome duplication, teleostei may have retained two copies of mstn genes and even up to four copies in salmonids due to additional genome duplication event. In sharp contrast to mammals, the different fish mstn orthologs are widely expressed with a tissue-specific expression pattern. Quantification of mstn mRNA in fish under different physiolog- ical conditions, demonstrates that endogenous expression of mstn paralogs is rarely related to fish muscle growth rate. In addition, attempts to inhibit MSTN activity did not consistently enhance muscle growth as in mammals. In vitro, MSTN stimulates myotube atrophy and inhibits proliferation but not differentiation of myogenic cells as in mammals. In conclusion, given the strong mstn expression non-muscle tissues of fish, we propose a new hypoth- esis stating that fish MSTN functions as a general inhibitors of cell proliferation and cell growth to control tissue mass but is not specialized into a strong muscle regulator. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction The Growth Differentiation Factor-8 (GDF-8) also known as myostatin, belongs to the Transforming Growth Factor beta (TGFb) superfamily (Derynck and Miyazono, 2008). The TGFb superfamily is composed of three subfamilies: the TGFb subfamily, the activin subfamily, and the BMP subfamily including myostatin. The TGFb superfamily members are involved in numerous cellular functions such as cell growth, proliferation, or differentiation. Myostatin (MSTN) first identified in 1997 in mouse by McPher- ron et al. (1997) is nearly expressed exclusively in skeletal muscle, and was reported to inhibit muscle growth as shown by mstn knock-out mice, and thus leading to the name ‘‘myostatin’’. Inter- estingly, a ‘‘doubled-muscled’’ phenotype was reported in several domesticated species such as Belgian blue and Piedmontaise cattle (Culley, 1807) or Texel sheep (Laville et al., 2004) prior to 1997. Be- fore the discovery of mstn, this phenotype was correlated to the presence of a mh (muscle hypertrophy) locus (Charlier et al., 1995). Genetic analysis first indicated that the position of the mstn gene maps to the interval containing the bovine mh locus (Smith et al., 1997). Subsequently, three publications demonstrate that the ‘‘double-muscle’’ phenotype in bovine was due to a mutation in mstn gene (McPherron et al., 1997; Grobet et al., 1997; Kambadur et al., 1997). More recently, muscle hypertrophy associated to mutations in the mstn gene have reported in human (Schuelke et al., 2004), dog (Mosher et al., 2007; Shelton and Engvall, 2007), and sheep (Johnson et al., 2005). The action of MSTN is largely believed to be mediated through inhibition of satellite cell activation, self-renewal and proliferation (McCroskery et al., 2003). The identification of a strong negative regulator of muscle mass such as MSTN offered the perspective to control muscle mass by targeting MSTN pathway. In an agronomic point of view, control- ling MSTN activity may help to improve the management of mus- cular growth of animals, as well as to define a new strategy to control both meat quantity and quality. Additionally, because the function of MSTN is conserved in humans, therapeutic approaches targeting MSTN activity may be an effective strategy for increasing muscle mass in several clinical situations (regeneration, cachexia, etc.). For the first time since the identification of fish mstn gene in 2001 (Maccatrozzo et al., 2001; Rescan et al., 2001; Roberts and Goetz, 2001; Rodgers et al., 2001) we reviewed the myostatin data obtained in fish. To date, numerous sequences of fish mstn genes are available, revealing the presence of up to four paralogs with a well-conserved protein sequences. However the expression patterns and regulation of mstn in fish are different from those 0016-6480/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygcen.2013.08.012 ⇑ Corresponding author. Fax: +33 223485020. E-mail address: Jean-Charles.Gabillard@rennes.inra.fr (J.-C. Gabillard). General and Comparative Endocrinology 194 (2013) 45–54 Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen