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Myostatin Inhibitors Explained
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1: Exp Neurol. 2009 Mar 11. [Epub ahead of print] Links
A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis.
Morrison BM, Lachey JL, Warsing LC, Ting BL, Pullen AE, Underwood KW, Kumar R, Sako D, Grinberg A, Wong V, Calantuoni E, Seehra JS, Wagner KR.
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.
A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis.
Morrison BM, Lachey JL, Warsing LC, Ting BL, Pullen AE, Underwood KW, Kumar R, Sako D, Grinberg A, Wong V, Calantuoni E, Seehra JS, Wagner KR.
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
Amyotrophic lateral sclerosis (ALS) is a neurologic disease characterized by progressive weakness that results in death within a few years of onset by respiratory failure. Myostatin is a member of the TGF-beta superfamily that is predominantly expressed in muscle and acts as a negative regulator of muscle growth. Attenuating myostatin has previously been shown to produce increased muscle mass and strength in normal and disease animal models. In this study, a mouse model of ALS (SOD1(G93A) transgenic mice) was treated with a soluble activin receptor, type IIB (ActRIIB.mFc) which is a putative endogenous signaling receptor for myostatin in addition to other ligands of the TGF-beta superfamily. ActRIIB.mFc treatment produces a delay in the onset of weakness, an increase in body weight and grip strength, and an enlargement of muscle size whether initiated pre-symptomatically or after symptom onset. Treatment with ActRIIB.mFc did not increase survival or neuromuscular junction innervation in SOD1(G93A) transgenic mice. Pharmacologic treatment with ActRIIB.mFc was superior in all measurements to genetic deletion of myostatin in SOD1(G93A) transgenic mice. The improved function of SOD1(G93A) transgenic mice following treatment with ActRIIB.mFc is encouraging for the development of TGF-beta pathway inhibitors to increase muscle strength in patients with ALS.
Monitor of the myostatin autocrine action during differentiation of embryonic chicken myoblasts into myotubes: effect of IGF-I.
Kurokawa M, Sato F, Aramaki S, Soh T, Yamauchi N, Hattori MA.
Laboratory of Reproductive Physiology and Biotechnology, Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan.
Myogenesis is regulated through the proliferation and differentiation of myoblasts expressing myostatin which functions as a negative regulator by generating Smad signals. Here, we monitored the autocrine action of myostatin in quiescent chicken myoblasts transfected with the Smad-mediated promoter reporter vector to evaluate the modulation of several growth factors. During differentiation of myoblasts into myotubes, stretched and spherical types of myoblasts were observed at 12 h after induction, at which the promoter activity began to increase. Maximal promoter activity was observed at approximately 30 h. Multinucleated myotubes were markedly formed at 72 h, but the activity was very low. IGF-I, known as a positive regulator of myogenesis, increased the promoter activity, but the increase was rather small at its high concentration (100 ng/ml). IGF-I significantly increased the level of myostatin transcript in myoblasts and newly formed myotubes at 24 h, but not at 36 h. However, the cell fusion of myoblasts was not accelerated in the presence of IGF-I. Consequently, this study indicates that the autocrine action of myostatin is partially enhanced by IGF-I through increasing its expression.
Kurokawa M, Sato F, Aramaki S, Soh T, Yamauchi N, Hattori MA.
Laboratory of Reproductive Physiology and Biotechnology, Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan.
Myogenesis is regulated through the proliferation and differentiation of myoblasts expressing myostatin which functions as a negative regulator by generating Smad signals. Here, we monitored the autocrine action of myostatin in quiescent chicken myoblasts transfected with the Smad-mediated promoter reporter vector to evaluate the modulation of several growth factors. During differentiation of myoblasts into myotubes, stretched and spherical types of myoblasts were observed at 12 h after induction, at which the promoter activity began to increase. Maximal promoter activity was observed at approximately 30 h. Multinucleated myotubes were markedly formed at 72 h, but the activity was very low. IGF-I, known as a positive regulator of myogenesis, increased the promoter activity, but the increase was rather small at its high concentration (100 ng/ml). IGF-I significantly increased the level of myostatin transcript in myoblasts and newly formed myotubes at 24 h, but not at 36 h. However, the cell fusion of myoblasts was not accelerated in the presence of IGF-I. Consequently, this study indicates that the autocrine action of myostatin is partially enhanced by IGF-I through increasing its expression.
