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• W2753103539 abstract "•GJG significantly increased the body and muscle weight of DBA/2-mdx regardless of gender.•GJG significantly increased myofiber size but not myofiber number.•GJG did not affect muscle regeneration or pathological feature of DBA/2-mdx. Go-sha-jinki-gan (GJG), a traditional Japanese herbal medicine has a clinical implication to alleviate age-related symptoms, especially in some motor disorders. However, the scientific evidence is limited, and there is a possibility to expand the medical application range of GJG. Using senescence-accelerated mice, our group showed that GJG exerted an effect to prevent sarcopenia, the aged-related loss of skeletal muscle. Because muscular dystrophy is characterized by a progressive loss of skeletal muscle, we examined the effects of GJG on a mouse model of muscular dystrophy. Using a newly established mouse model for Duchenne muscular dystrophy (DMD), DBA/2-mdx, we showed that GJG significantly increased the body and skeletal muscle weights in comparison to the control DBA/2-mdx mice, regardless of gender. The increased skeletal muscle mass resulted from an increment in the myofiber size, but not from the myofiber number. Both the skeletal muscle regenerative ability and the accumulation of fibrosis (the dystrophic pathology) in GJG-fed DBA/2-mdx mice were comparable to those in control DBA/2-mdx mice, suggesting that the cellular target of GJG is myofibers, with no contribution from the muscle satellite cells neither in an direct nor in an indirect manner. Taken together, GJG increased the skeletal muscle mass in a mouse model of muscular dystrophy, in addition to our previously tested sarcopenia mouse model. Go-sha-jinki-gan (GJG), a traditional Japanese herbal medicine has a clinical implication to alleviate age-related symptoms, especially in some motor disorders. However, the scientific evidence is limited, and there is a possibility to expand the medical application range of GJG. Using senescence-accelerated mice, our group showed that GJG exerted an effect to prevent sarcopenia, the aged-related loss of skeletal muscle. Because muscular dystrophy is characterized by a progressive loss of skeletal muscle, we examined the effects of GJG on a mouse model of muscular dystrophy. Using a newly established mouse model for Duchenne muscular dystrophy (DMD), DBA/2-mdx, we showed that GJG significantly increased the body and skeletal muscle weights in comparison to the control DBA/2-mdx mice, regardless of gender. The increased skeletal muscle mass resulted from an increment in the myofiber size, but not from the myofiber number. Both the skeletal muscle regenerative ability and the accumulation of fibrosis (the dystrophic pathology) in GJG-fed DBA/2-mdx mice were comparable to those in control DBA/2-mdx mice, suggesting that the cellular target of GJG is myofibers, with no contribution from the muscle satellite cells neither in an direct nor in an indirect manner. Taken together, GJG increased the skeletal muscle mass in a mouse model of muscular dystrophy, in addition to our previously tested sarcopenia mouse model. Skeletal muscle consists mainly of multinuclear myofibers and is known for a remarkable regenerative ability. In mammalians, myofibers are the terminally differentiated cells in an irreversible cell cycle state; therefore, the regenerative ability depends on the myogenic-primed mononuclear cells [[1]Crist C.G. Montarras D. Buckingham M. Muscle satellite cells are primed for myogenesis but maintain quiescence with sequestration of Myf5 mRNA targeted by microRNA-31 in mRNP granules.Cell Stem Cell. 2012; 11: 118-126Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar], called muscle satellite cells. Muscle satellite cells are localized in a unique anatomical position and are defined by Pax7 (Paired box 7) expression [2Mauro A. Satellite cell of skeletal muscle fibers.J Biophys Biochem Cytol. 1961; 9: 493-495Crossref PubMed Scopus (2712) Google Scholar, 3Seale P. Sabourin L.A. Girgis-Gabardo A. Mansouri A. Gruss P. Rudnicki M.A. Pax7 is required for the specification of myogenic satellite cells.Cell. 2000; 102: 777-786Abstract Full Text Full Text PDF PubMed Scopus (1660) Google Scholar]. New myofiber generation depends completely on the muscle satellite cells. While the size of myofibers is reversible, and the states are known as muscle atrophy or hypertrophy with no satellite cell contribution [4McCarthy J.J. Mula J. Miyazaki M. Erfani R. Garrison K. Farooqui A.B. et al.Effective fiber hypertrophy in satellite cell-depleted skeletal muscle.Development. 2011; 138: 3657-3666Crossref PubMed Scopus (444) Google Scholar, 5Fry C.S. Lee J.D. Jackson J.R. Kirby T.J. Stasko S.A. Liu H. et al.Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy.FASEB J. 2014; 28: 1654-1665Crossref PubMed Scopus (191) Google Scholar, 6Jackson J.R. Mula J. Kirby T.J. Fry C.S. Lee J.D. Ubele M.F. et al.Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy.Am J Physiol Cell Physiol. 2012; 303: C854-C861Crossref PubMed Scopus (109) Google Scholar]. Immobilization and some diseases, including cancer cachexia, type I diabetes, and sepsis, often lead to the atrophy of myofibers [[7]Ciciliot S. Rossi A.C. Dyar K.A. Blaauw B. Schiaffino S. Muscle type and fiber type specificity in muscle wasting.Int J Biochem Cell Biol. 2013; 45: 2191-2199Crossref PubMed Scopus (328) Google Scholar]. The aged-related loss and atrophy of skeletal muscle mass is known as sarcopenia. Conversely, resistance training increases skeletal muscle mass by causing hypertrophy of myofibers. Besides resistance training, some intrinsic factors regulate the size of myofibers. For example, a well-known promoting factor of muscle hypertrophy is insulin-like growth factor (IGF1), and an inhibiting factor is myostatin. IGF-1 signaling induces muscle hypertrophy via phosphatidylinositol-3-kinase (PI3K) and protein kinase B (PKB, also known as Akt). Akt signaling eventually promotes protein synthesis. Negative signaling of myostatin, a member of the transforming growth factor β (TGF-β) superfamily, regulates skeletal muscle mass via activin receptor IIB/activin-like kinase (ActRIIB/ALK4/5) receptors. Myostatin-null animals show remarkable increases in skeletal muscle mass and size of myofibers [8McPherron A.C. Lee S.J. Double muscling in cattle due to mutations in the myostatin gene.Proc Natl Acad Sci U. S. A. 1997; 94: 12457-12461Crossref PubMed Scopus (1590) Google Scholar, 9McPherron A.C. Lawler A.M. Lee S.J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.Nature. 1997; 387: 83-90Crossref PubMed Scopus (3175) Google Scholar]. In myogenic cells, myostatin acts on myofibers but does not influence satellites cell/progenitors activity, suggesting that myostatin-inhibition directly affects myofibers and that the increased muscle mass play beneficial roles in preventing muscular dystrophy [[10]Amthor H. Otto A. Vulin A. Rochat A. Dumonceaux J. Garcia L. et al.Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity.Proc Natl Acad Sci U. S. A. 2009; 106: 7479-7484Crossref PubMed Scopus (148) Google Scholar]. One representative muscular dystrophy is Duchenne muscular dystrophy (DMD), cause by a mutation in the Dystrophin gene. Mdx mice (C57BL/10ScSn-Dmdmdx, hereafter B10-mdx) also have a mutation in the dystrophin gene and have been widely used as a mouse model for DMD. B10-mdx has been used in a large number of studies on pathologies of and therapeutic approach for DMD [[11]Bulfield G. Siller W.G. Wight P.A. Moore K.J. X chromosome-linked muscular dystrophy (mdx) in the mouse.Proc Natl Acad Sci U. S. A. 1984; 81: 1189-1192Crossref PubMed Scopus (1389) Google Scholar]. The effect of myostatin has been also evaluated using B10-mdx mice [[12]Bogdanovich S. Krag T.O. Barton E.R. Morris L.D. Whittemore L.A. Ahima R.S. et al.Functional improvement of dystrophic muscle by myostatin blockade.Nature. 2002; 420: 418-421Crossref PubMed Scopus (721) Google Scholar]. The diaphragm, the tissue most frequently used in pathological studies, undergoes extensive progression of degeneration, mineralization, and replacement by fibrosis and fat. In contrast, the limb muscles of B10-mdx show little fibrosis and fat replacement. Furthermore, in contrast to the DMD patients, the body and skeletal muscle weights of B10-mdx are reported heavier than those of control mice, meaning that B10-mdx does not adequately model to elucidate the therapeutic effects especially on the weight of skeletal muscle. Based on the background, a more suitable model had been required for investigating DMD treatments [[13]Rodrigues M. Echigoya Y. Fukada S.I. Yokota T. Current translational research and murine models for Duchenne muscular dystrophy.J Neuromuscul Dis. 2016; 3: 29-48Crossref PubMed Scopus (39) Google Scholar]. We previously found that DBA/2 inbred mice exhibited a relatively normal skeletal muscle regenerative ability after a single injury but showed a remarkable loss of skeletal muscle mass after repeated injuries. Because muscle regeneration and degeneration recurred spontaneously in mdx mice, we generated DBA/2-mdx. Intriguingly, DBA/2-mdx showed remarkable decreases in muscle and body weights [[14]Fukada S. Morikawa D. Yamamoto Y. Yoshida T. Sumie N. Yamaguchi M. et al.Genetic background affects properties of satellite cells and mdx phenotypes.Am J Pathol. 2010; 176: 2414-2424Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Two different laboratories (Children's National Medical Center and The Jackson Laboratory) assessed and reproduced the decrease in the muscle weight, body weight, and a lower regenerative potential of DBA/2-mdx compared to B10-mdx [[15]Coley W.D. Bogdanik L. Vila M.C. Yu Q. Van Der Meulen J.H. Rayavarapu S. et al.Effect of genetic background on the dystrophic phenotype in mdx mice.Hum Mol Genet. 2016; 25: 130-145Crossref PubMed Scopus (120) Google Scholar]. Thus, using the DBA/2-mdx mice should be a more suitable model in evaluating dystrophic changes, including during the recovery of skeletal muscle mass with new therapeutic approaches than using the B10-mdx [[16]Ito T. Ogawa R. Uezumi A. Ohtani T. Watanabe Y. Tsujikawa K. et al.Imatinib attenuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors.Neuromuscul Disord. 2013; 23: 349-356Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar]. Currently, there are few known therapeutic approaches for DMD. Although the effects of herbal medicines on DMD patients have received some attentions [[17]Urtizberea J.A. Fan Q.S. Vroom E. Recan D. Kaplan J.C. Looking under every rock: Duchenne muscular dystrophy and traditional Chinese medicine.Neuromuscul Disord. 2003; 13: 705-707Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar], little scientific evidence is available. Recently, Kishida et al. reported that Go-sha-jinki-gan (GJG), a traditional Japanese herbal medicine, protected muscle tissues against sarcopenia in a senescence-accelerated mouse, SAMP8 [[18]Takeda T. Matsushita T. Kurozumi M. Takemura K. Higuchi K. Hosokawa M. Pathobiology of the senescence-accelerated mouse (SAM).Exp Gerontol. 1997; 32: 117-127Crossref PubMed Scopus (171) Google Scholar], a widely-used model in aging research exhibiting several accelerated aging characteristics [[19]Kishida Y. Kagawa S. Arimitsu J. Nakanishi M. Sakashita N. Otsuka S. et al.Go-sha-jinki-Gan (GJG), a traditional Japanese herbal medicine, protects against sarcopenia in senescence-accelerated mice.Phytomedicine. 2015; 22: 16-22Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. GJG is composed of 10 herbals in a fixed proportion. This medicine has been used to alleviate various types of age-related conditions in locomotion, and no severe adverse effects in humans have been reported. In addition, studies using anti-myostatin and IGF-1 have suggested that the increased skeletal muscle mass improved dystrophic symptoms. Based on such prior results, it is useful to examine the effects of GJG on the skeletal muscle mass and the progression of muscular dystrophy. Here, we examined the effects of GJG on the muscle weight and pathology of DBA/2-mdx and found an effect of GJG on the muscle weight. Specifically, the myofiber size increased, while the number remained unchanged. On the other hand, immunohistochemical evaluations support that GJG did not alter muscle regeneration or the pathological conditions. Taken together, although GJG did not improve any dystrophic condition, it had expanded the size of skeletal muscle size in a muscular dystrophy mouse model, similarly to the previously obtained results in senescence-accelerated mice. Spray-dried, water-extracted GJG powder was obtained from Tsumura & Co. (Tokyo, Japan). MF feed containing 4% GJG was produced by Oriental Yeast Co., Ltd. MF without GJG was also purchased from Oriental Yeast Co. and used for a control. In the previous study, the dose dependent maximum effect of GJG was 4% GJG, among the tested dosages of 0.5–4% [[20]Nakanishi M. Nakae A. Kishida Y. Baba K. Sakashita N. Shibata M. et al.Go-sha-jinki-Gan (GJG) ameliorates allodynia in chronic constriction injury-model mice via suppression of TNF-alpha expression in the spinal cord.Mol Pain. 2016; 12Crossref PubMed Scopus (20) Google Scholar]. Hence, in the present study, we treated DBA/2-mdx mice with 4% GJG food. Normal DBA/2 mice were purchased from Charles River Japan (Kanagawa, Japan). The DBA/2-mdx mice [[14]Fukada S. Morikawa D. Yamamoto Y. Yoshida T. Sumie N. Yamaguchi M. et al.Genetic background affects properties of satellite cells and mdx phenotypes.Am J Pathol. 2010; 176: 2414-2424Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar] used were backcrossed more than ten generations. Genotyping was performed according to a previous report [[21]Amalfitano A. Chamberlain J.S. The mdx-amplification-resistant mutation system assay, a simple and rapid polymerase chain reaction-based detection of the mdx allele.Muscle Nerve. 1996; 19: 1549-1553Crossref PubMed Scopus (83) Google Scholar]. All procedures for experimental animal use were approved by the Experimental Animal Care and Use Committee at Osaka University. Tibialis anterior (TA), gastrocnemius (GC), quadriceps femoris (Qu), and diaphragm muscles were isolated and frozen in liquid nitrogen-cooled isopentane (Wako Pure Chemical Industries, Osaka, Japan). Cryosections (10 μm in thickness) were stained with H&E. Cryosections (6 μm in thickness) were fixed in cooled acetone for 10 min. After blocking with M.O.M. kit (Vector Laboratories, Burlingame, CA, USA), the sections were incubated with anti-embryonic myosin heavy chain (eMyHC) antibodies (clone F1.652, Developmental Studies Hybridoma Bank, Iowa City, IA, USA). After the first staining at 4 °C overnight, the sections were reacted with secondary antibodies (Molecular Probes, Eugene, OR, USA). The signals were recorded photographically using a BZ-X710 fluorescence microscope (Keyence, Tokyo, Japan). For the measurement of fibrotic area, cryosections (6 μm) were incubated with anti-collagen type I antibody (Bio-Rad Laboratories Inc., Hercules, CA, USA). After the first staining at 4 °C overnight, sections were incubated with a secondary antibody conjugated with Alexa 488 or 546 (Molecular Probes), and then coverslipped using Vectashield (Vector Laboratories). The signals were recorded photographically using a BZ-X700 fluorescence microscope (Keyence). For the measurement of the myofiber size, the cryosections were stained with anti-laminin α2 antibody (clone 4H8-2, Enzo Life Sciences, Inc. Plymouth Meeting, PA, USA). The subsequent protocol used was identical to that used for the fibrotic areal measurement. Values were expressed as means ± SD. Statistical significance was assessed by Student's t test. A probability of less than 5% (p < 0.05) or 1% (p < 0.01) was considered statistically significant. Both Duchenne muscular dystrophy (DMD) patients and widely used mdx mice (C57BL/10, hereafter B10-mdx) have a mutation in the dystrophin genes, but the symptoms are different. One of the phenotypes that are not shared is the weight of the skeletal muscle. In contrast to DMD patients, most of the muscles of B10-mdx exhibit hypertrophy and increased skeletal muscle mass. On the other hand, DBA/2-mdx mice showed a severe decrease in muscle weight, indicating that DBA/2-mdx is a more suitable model to determine whether or not GJG has a clinical implication in regulating skeletal muscle weight [[14]Fukada S. Morikawa D. Yamamoto Y. Yoshida T. Sumie N. Yamaguchi M. et al.Genetic background affects properties of satellite cells and mdx phenotypes.Am J Pathol. 2010; 176: 2414-2424Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. First, we elucidated the effect of GJG on the body and muscle weights of DBA/2- mdx. Onset of muscular dystrophy typically starts around 3–4 wks in mdx mice. In order to examine the efficacy of GJG prior to the onset, we prepared pregnant mice and fed chow including or not including GJG, from five to three days before parturition (Fig. 1A). After weaning, the offspring continued to consume feed with or without GJG. Eight weeks of feeding after the birth, the offspring were scarified and the muscles were analyzed. As shown in Fig. 1B, the body weight of GJG-fed DBA/2-mdx increased compared to that of the control-fed DBA/2-mdx. The limb muscles of GJG-fed mice were also heavier than those of the control-fed mice regardless of gender (Fig. 1C). Thus, GJG increased both body and skeletal muscle weights in DBA/2-mdx. Generally speaking, increased muscle weight results from an increment in the number or size of myofibers, or both. Hence, we measured the number and size of myofibers in the gastrocnemius muscles. As shown in Fig. 2A, GJG treatment remarkably increased myofiber size regardless of gender. On the other hand, the number of myofibers in the GJG group was comparable to that of the control group, or tended to be reduced (Fig. 2B). Those results indicate that the increased muscle weight in the GJG group results from the increase in myofiber size. Next, in order to elucidate the effect of GJG on muscle regeneration, newly generating myofibers were visualized with an antibody to embryonic myosin heavy chain (eMyHC). As shown in Fig. 3A, the eMyHC-positive area in GJG-fed mice was similar to that in the control-treated DBA/2-mdx. Quantitative analyses also showed that the eMyHC-positive area in the GJG-fed muscle was comparable to the control muscle regardless of gender (Fig. 3B), suggesting that skeletal muscle regeneration was not promoted by GJG. It is considered that the increased muscle weight and size exert an impact on dystrophic pathology. Myostatin also improved dystrophic pathology with direct effects on myofibers but not on muscle satellite cells [[10]Amthor H. Otto A. Vulin A. Rochat A. Dumonceaux J. Garcia L. et al.Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity.Proc Natl Acad Sci U. S. A. 2009; 106: 7479-7484Crossref PubMed Scopus (148) Google Scholar]. Therefore, we evaluated the effects of GJG on dystrophic pathology in DBA/2-mdx mice. The fibrotic area was quantified by staining with anti-collagen type I antibody. As shown in Fig 4A and B, there was no significant difference in the collagen type I-positive areas between control and GJG-fed groups regardless of gender, suggesting that the GJG treatment did not ameliorate the dystrophic condition. Further, histological analyses by H&E staining suggested that there was no notable improvement of dystrophic pathologies by GJG in DBA/2-mdx mice (Fig. 4C). To confirm the effect of GJG at the onset of muscular dystrophy, we treated DBA/2-mdx with GJG after weaning. The food GJG treatment started from adult age of 4 weeks and ended during the adult age of 20 weeks. One group was fed with GJG and the control received a typical chow for 16 weeks (Fig. 5A). As shown in Fig. 5B, both males and females of the GJG-fed group showed an increase in the body weight compared with the control mice. Individual differences obscured the significant difference between the control and GJG groups, but relative analyses based on the control littermates showed that GJG significantly increased muscle weight compared to control mice (Fig. 5C). These results suggest that ingredients in GJG is capable of increasing the skeletal muscle mass, even at the time of muscular dystrophy onset. Kishida and colleagues showed that GJG increased the size of myofibers in senescence-accelerated mice (SAMP8). Here, we obtained a similar result in a DMD-model mouse, DBA/2-mdx, indicating that the effect of GJG on skeletal muscle mass is reproducible in a different animal model. Because the GJG group showed no significant difference in the food intake compared to the control group [[19]Kishida Y. Kagawa S. Arimitsu J. Nakanishi M. Sakashita N. Otsuka S. et al.Go-sha-jinki-Gan (GJG), a traditional Japanese herbal medicine, protects against sarcopenia in senescence-accelerated mice.Phytomedicine. 2015; 22: 16-22Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar], nutritional status should not have affected the results. The efficacy of GJG on sarcopenia animals is suggested to occur through activation of the Akt/mechanistic target of rapamycin (mTOR) pathway [[19]Kishida Y. Kagawa S. Arimitsu J. Nakanishi M. Sakashita N. Otsuka S. et al.Go-sha-jinki-Gan (GJG), a traditional Japanese herbal medicine, protects against sarcopenia in senescence-accelerated mice.Phytomedicine. 2015; 22: 16-22Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. A potential mechanism of Akt/mTOR activation is via an increased serum IGF1 level. It was reported that muscle-specific expression of IGF-1 counters muscle decline even in mdx mice [[22]Barton E.R. Morris L. Musaro A. Rosenthal N. Sweeney H.L. Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice.J Cell Biol. 2002; 157: 137-148Crossref PubMed Scopus (398) Google Scholar]. The increased muscle weight and myofiber size in DBA/2-mdx might be explained by similar mechanisms. However, it was shown that muscle-specific expression of IGF-1 decreased the replacement of muscle by fibrosis in the diaphragm of B10-mdx mice. IGF-1 is a known regulator of muscle regeneration [[23]Charge S.B. Rudnicki M.A. Cellular and molecular regulation of muscle regeneration.Physiol Rev. 2004; 84: 209-238Crossref PubMed Scopus (1982) Google Scholar]. In our analyses, areas of muscle regeneration (eMyHC areas) observed in the GJG-fed groups were not different from the control. In addition, compared with sarcopenia, dystrophic muscles seem to exhibit induction of the anabolic pathway [[24]Sakuma K. Aoi W. Yamaguchi A. The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy.Front Aging Neurosci. 2014; 6: 230Crossref PubMed Scopus (47) Google Scholar]. It is reported that rapamycin (which is an inhibitor of mTOR) ameliorates dystrophic phenotypes in B10-mdx [[25]Eghtesad S. Jhunjhunwala S. Little S.R. Clemens P.R. Rapamycin ameliorates dystrophic phenotype in mdx mouse skeletal muscle.Mol Med. 2011; 17: 917-924Crossref PubMed Scopus (53) Google Scholar], meaning that accelerated mTOR pathways exacerbate dystrophic phenotypes. In fact, De Palma et al. showed the hyperactivation of Akt and mTOR signaling in tibialis anterior and diaphragm muscles of B10-mdx mice [[26]De Palma C. Morisi F. Cheli S. Pambianco S. Cappello V. Vezzoli M. et al.Autophagy as a new therapeutic target in Duchenne muscular dystrophy.Cell Death Dis. 2012; 3: e418Crossref PubMed Scopus (172) Google Scholar]. Those results suggest that the contribution of the mTOR-dependent signaling pathway is different in sarcopenia and in muscular dystrophy [[24]Sakuma K. Aoi W. Yamaguchi A. The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy.Front Aging Neurosci. 2014; 6: 230Crossref PubMed Scopus (47) Google Scholar]. Collectively, the effect of GJG on the increased weight of DBA/2-mdx muscles seems not to be mediated by Akt/mTOR pathways. Muscle satellite cells are essential for regeneration of the skeletal muscle. The lower regenerative ability of the satellite cells is considered to be one reason why DBA/2-mdx mice show severe phenotypes compared with C57BL/10-mdx [[14]Fukada S. Morikawa D. Yamamoto Y. Yoshida T. Sumie N. Yamaguchi M. et al.Genetic background affects properties of satellite cells and mdx phenotypes.Am J Pathol. 2010; 176: 2414-2424Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Recently, we reported a reduced number of revertant fibers derived from satellite cells, also indicating the lower regenerative ability of satellite cells in DBA/2-mdx [[27]Rodrigues M. Echigoya Y. Maruyama R. Lim K.R. Fukada S.I. Yokota T. Impaired regenerative capacity and lower revertant fibre expansion in dystrophin-deficient mdx muscles on DBA/2 background.Sci Rep. 2016; 6: 38371Crossref PubMed Scopus (30) Google Scholar]. Coley also pointed out the impaired regenerative ability of satellite cells in DBA/2-mdx because the number of myofibers with central nuclei (indicating regenerated myofibers) is smaller than in B10-mdx [[15]Coley W.D. Bogdanik L. Vila M.C. Yu Q. Van Der Meulen J.H. Rayavarapu S. et al.Effect of genetic background on the dystrophic phenotype in mdx mice.Hum Mol Genet. 2016; 25: 130-145Crossref PubMed Scopus (120) Google Scholar]. As shown here, we did not observe a significant acceleration of regenerative ability in the GJG group, suggesting that GJG did not target satellite cell/progenitors. In contrast to the genetic loss or pharmacological inhibition of myostatin, GJG did not alleviate the disease symptoms of the dystrophy (e.g., fibrosis and fat accumulation). Intriguingly, it is reported that the inhibition of myostatin increases the number of apoptotic fibroblasts in a limb muscle of B10-mdx mice, accompanied by a reduced areas of fibrosis and fat accumulation [[28]Bo Li Z. Zhang J. Wagner K.R. Inhibition of myostatin reverses muscle fibrosis through apoptosis.J Cell Sci. 2012; 125: 3957-3965Crossref PubMed Scopus (64) Google Scholar]. In the skeletal muscle, a Pdgfrα-positive mesenchymal progenitor is the common origin of fibrosis and fat accumulation [16Ito T. Ogawa R. Uezumi A. Ohtani T. Watanabe Y. Tsujikawa K. et al.Imatinib attenuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors.Neuromuscul Disord. 2013; 23: 349-356Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 29Uezumi A. Fukada S. Yamamoto N. Takeda S. Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle.Nat Cell Biol. 2010; 12: 143-152Crossref PubMed Scopus (813) Google Scholar, 30Uezumi A. Ito T. Morikawa D. Shimizu N. Yoneda T. Segawa M. et al.Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle.J Cell Sci. 2011; 124: 3654-3664Crossref PubMed Scopus (392) Google Scholar, 31Uezumi A. Fukada S. Yamamoto N. Ikemoto-Uezumi M. Nakatani M. Morita M. et al.Identification and characterization of PDGFRalpha(+) mesenchymal progenitors in human skeletal muscle.Cell Death Dis. 2014; 5: e1186Crossref PubMed Scopus (180) Google Scholar], suggesting that a mesenchymal progenitor is the target of myostatin. Thus, although GJG did not improve dystrophic pathologies, GJG treatments combined with another approach targeting mesenchymal progenitors may show a therapeutic efficacy. In conclusion, GJG increased the skeletal muscle mass in a severe DMD model mouse. One important issue now is to identify the compound(s) that affected the skeletal muscle mass which may enable a development of a therapeutic strategy for muscle-related diseases especially requires the regain of skeletal muscle mass. The authors declare no conflict of interest. We thank Katherine Ono for comments on the manuscript. This work was supported by Tsumura & Co. Tokyo Japan and neurological diseases and mental health and a research grant (28-6)." @default.
• W2753103539 created "2017-09-15" @default.
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• W2753103539 title "An herbal medicine, Go-sha-jinki-gan (GJG), increases muscle weight in severe muscle dystrophy model mice" @default.
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