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1.
J Pharmacol Exp Ther ; 368(3): 435-445, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30563942

RESUMEN

Follistatin is an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor-ß superfamily and may therefore have therapeutic potential for neuromuscular diseases. Here, we sought to determine the suitability of a newly engineered follistatin fusion protein (FST288-Fc) to promote localized, rather than systemic, growth of skeletal muscle by capitalizing on the intrinsic heparin-binding ability of the follistatin-288 isoform. As determined by surface plasmon resonance and cell-based assays, FST288-Fc binds to activin A, activin B, myostatin (growth differentiation factor GDF8), and GDF11 with high affinity and neutralizes their activity in vitro. Intramuscular administration of FST288-Fc in mice induced robust, dose-dependent growth of the targeted muscle but not of surrounding or contralateral muscles, in contrast to the systemic effects of a locally administered fusion protein incorporating activin receptor type IIB (ActRIIB-Fc). Furthermore, systemic administration of FST288-Fc in mice did not alter muscle mass or body composition as determined by NMR, which again contrasts with the pronounced systemic activity of ActRIIB-Fc when administered by the same route. Subsequent analysis revealed that FST288-Fc in the circulation undergoes rapid proteolysis, thereby restricting its activity to individual muscles targeted by intramuscular administration. These results indicate that FST288-Fc can produce localized growth of skeletal muscle in a targeted manner with reduced potential for undesirable systemic effects. Thus, FST288-Fc and similar agents may be beneficial in the treatment of disorders with muscle atrophy that is focal, asymmetric, or otherwise heterogeneous.


Asunto(s)
Folistatina/administración & dosificación , Inmunoglobulina G/administración & dosificación , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/crecimiento & desarrollo , Proteínas Recombinantes de Fusión/administración & dosificación , Secuencia de Aminoácidos , Animales , Relación Dosis-Respuesta a Droga , Folistatina/genética , Folistatina/metabolismo , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Inyecciones Intramusculares , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Estructura Secundaria de Proteína , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo
2.
Front Physiol ; 9: 515, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29881353

RESUMEN

Degenerative myopathies typically display a decline in satellite cells coupled with a replacement of muscle fibers by fat and fibrosis. During this pathological remodeling, satellite cells are present at lower numbers and do not display a proper regenerative function. Whether a decline in satellite cells directly contributes to disease progression or is a secondary result is unknown. In order to dissect these processes, we used a genetic model to reduce the satellite cell population by ~70-80% which leads to a nearly complete loss of regenerative potential. We observe that while no overt tissue damage is observed following satellite cell depletion, muscle fibers atrophy accompanied by changes in the stem cell niche cellular composition. Treatment of these mice with an Activin receptor type-2B (AcvR2B) pathway blocker reverses muscle fiber atrophy as expected, but also restores regenerative potential of the remaining satellite cells. These findings demonstrate that in addition to controlling fiber size, the AcvR2B pathway acts to regulate the muscle stem cell niche providing a more favorable environment for muscle regeneration.

3.
Muscle Nerve ; 49(6): 829-35, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24752469

RESUMEN

INTRODUCTION: Sensitive, non-invasive techniques are needed that can provide biomarkers of disease status and the effects of therapy in muscular dystrophy. METHODS: We evaluated electrical impedance myography (EIM) to serve in this role by studying 2-month-old and 18-month-old mdx and wild-type (WT) animals (10 animals in each of 4 groups). RESULTS: Marked differences were observed in EIM values between mdx and WT animals; the differences were more pronounced between the older age groups (e.g., reactance of 92.6 ± 4.3 Ω for mdx animals vs. 130 ± 4.1 Ω for WT animals, P<0.001). In addition, in vivo EIM parameters correlated significantly with the extent of connective tissue deposition in the mdx animals. CONCLUSIONS: EIM has the potential to serve as a valuable non-invasive method for evaluating muscular dystrophy. It can be a useful biomarker to assist with therapeutic testing in both pre-clinical and clinical studies.


Asunto(s)
Impedancia Eléctrica , Electromiografía/métodos , Músculo Esquelético/fisiopatología , Distrofias Musculares/fisiopatología , Factores de Edad , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Hidroxiprolina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofias Musculares/metabolismo , Distrofias Musculares/patología
4.
Am J Pathol ; 184(6): 1831-42, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24726641

RESUMEN

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.


Asunto(s)
Receptores de Activinas Tipo II/metabolismo , Proteínas Musculares/metabolismo , Miopatías Estructurales Congénitas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Transducción de Señal , Receptores de Activinas Tipo II/genética , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Mutantes , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Proto-Oncogénicas c-akt/genética , Células Satélite del Músculo Esquelético/patología
5.
Endocrinology ; 153(7): 3133-46, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22549226

RESUMEN

Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.


Asunto(s)
Receptores de Activinas Tipo II/metabolismo , Obesidad/metabolismo , Transactivadores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Ensayo de Inmunoadsorción Enzimática/métodos , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica/métodos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Receptores Activados del Proliferador del Peroxisoma , Resonancia por Plasmón de Superficie , Termogénesis , Tomografía Computarizada por Rayos X/métodos , Factores de Transcripción
6.
Muscle Nerve ; 43(5): 694-9, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21462203

RESUMEN

INTRODUCTION: In this study we investigated the action of RAP-031, a soluble activin receptor type IIB (ActRIIB) comprised of a form of the ActRIIB extracellular domain linked to a murine Fc, and the NF-κB inhibitor, ursodeoxycholic acid (UDCA), on the whole body strength of mdx mice. METHODS: The whole body tension (WBT) method of assessing the forward pulling tension (FPT) exerted by dystrophic (mdx) mice was used. RESULTS: RAP-031 produced a 41% increase in body mass and a 42.5% increase in FPT without altering the FPT normalized for body mass (WBT). Coadministration of RAP-031 with UDCA produced increases in FPT that were associated with an increase in WBT. CONCLUSIONS: Myostatin inhibition increases muscle mass without altering the fundamental weakness characteristic of dystrophic muscle. Cotreatment with an NF-κB inhibitor potentiates the effects of myostatin inhibition in improving FPT in mdx mice.


Asunto(s)
Receptores de Activinas Tipo II/fisiología , Tono Muscular/fisiología , Músculo Esquelético/fisiología , Distrofia Muscular Animal/fisiopatología , Receptores de Activinas Tipo II/farmacología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos mdx , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Tono Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Distrofia Muscular Animal/genética , Solubilidad
7.
Am J Pathol ; 178(3): 1287-97, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21356379

RESUMEN

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-ß superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.


Asunto(s)
Receptores de Activinas Tipo II/antagonistas & inhibidores , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofia Muscular Animal/fisiopatología , Recuperación de la Función/fisiología , Receptores de Activinas Tipo II/metabolismo , Animales , Fenómenos Biomecánicos , Peso Corporal , Creatina Quinasa/sangre , Hidroxiprolina/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Contracción Muscular/fisiología , Distrofia Muscular Animal/sangre , Distrofia Muscular Animal/patología , Tamaño de los Órganos
8.
Am J Pathol ; 178(2): 784-93, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21281811

RESUMEN

X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency.


Asunto(s)
Receptores de Activinas Tipo II/antagonistas & inhibidores , Longevidad/fisiología , Fuerza Muscular/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/deficiencia , Receptores de Activinas Tipo II/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiología , Gravitación , Fuerza de la Mano/fisiología , Longevidad/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Miostatina/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Análisis de Supervivencia
9.
J Clin Invest ; 121(1): 355-68, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21183787

RESUMEN

Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.


Asunto(s)
Hipotálamo/metabolismo , Leptina/metabolismo , Proteínas/metabolismo , Maduración Sexual/fisiología , Animales , Secuencia de Bases , Femenino , Fertilidad/genética , Fertilidad/fisiología , Expresión Génica , Humanos , Kisspeptinas , Leptina/deficiencia , Leptina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ratones Transgénicos , Neuronas/metabolismo , Embarazo , Proteínas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Leptina/deficiencia , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Maduración Sexual/genética , Transducción de Señal
10.
PLoS One ; 5(9): e12707, 2010 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-20856813

RESUMEN

BACKGROUND: Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment. METHODOLOGY AND PRINCIPAL FINDINGS: We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size. CONCLUSIONS AND SIGNIFICANCE: Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force.


Asunto(s)
Receptores de Activinas Tipo II/metabolismo , Regulación hacia Abajo , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Proteínas Proto-Oncogénicas c-akt/deficiencia , Receptores de Activinas Tipo II/antagonistas & inhibidores , Receptores de Activinas Tipo II/genética , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Muscular , Músculo Esquelético/enzimología , Atrofia Muscular/genética , Atrofia Muscular/fisiopatología , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal
11.
Endocrinology ; 151(9): 4289-300, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20573726

RESUMEN

Androgen deprivation, a consequence of hypogonadism, certain cancer treatments, or normal aging in men, leads to loss of muscle mass, increased adiposity, and osteoporosis. In the present study, using a soluble chimeric form of activin receptor type IIB (ActRIIB) we sought to offset the adverse effects of androgen deprivation on muscle, adipose tissue, and bone. Castrated (ORX) or sham-operated (SHAM) mice received either TBS [vehicle-treated (VEH)] or systemic administration of ActRIIB-mFc, a soluble fusion protein comprised of a form of the extracellular domain of ActRIIB fused to a murine IgG2aFc subunit. In vivo body composition imaging demonstrated that ActRIIB-mFc treatment results in increased lean tissue mass of 23% in SHAM mice [19.02 +/- 0.42 g (VEH) versus 23.43 +/- 0.35 g (ActRIIB-mFc), P < 0.00001] and 26% in ORX mice [15.59 +/- 0.26 g (VEH) versus 19.78 +/- 0.26 g (ActRIIB-mFc), P < 0.00001]. Treatment also caused a decrease in adiposity of 30% in SHAM mice [5.03 +/- 0.48 g (VEH) versus 3.53 +/- 0.19 g (ActRIIB-mFc), NS] and 36% in ORX mice [7.12 +/- 0.53 g (VEH) versus 4.57 +/- 0.28 g (ActRIIB-mFc), P < 0.001]. These changes were also accompanied by altered serum levels of leptin, adiponectin, and insulin, as well as by prevention of steatosis (fatty liver) in ActRIIB-mFc-treated ORX mice. Finally, ActRIIB-mFc prevented loss of bone mass in ORX mice as assessed by whole body dual x-ray absorptiometry and micro-computed tomography of proximal tibias. The data demonstrate that treatment with ActRIIB-mFc restored muscle mass, adiposity, and bone quality to normal levels in a mouse model of androgen deprivation, thereby alleviating multiple adverse consequences of such therapy.


Asunto(s)
Receptores de Activinas Tipo II/farmacología , Antagonistas de Andrógenos/farmacología , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Receptores de Activinas Tipo II/genética , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Línea Celular , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Inmunoglobulina G/genética , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Obesidad/sangre , Obesidad/prevención & control , Orquiectomía , Distribución Aleatoria , Proteínas Recombinantes de Fusión/farmacología , Solubilidad
12.
J Appl Physiol (1985) ; 109(3): 635-42, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20466801

RESUMEN

This is the first report that inhibition of negative regulators of skeletal muscle by a soluble form of activin type IIB receptor (ACE-031) increases muscle mass independent of fiber-type expression. This finding is distinct from the effects of selective pharmacological inhibition of myostatin (GDF-8), which predominantly targets type II fibers. In our study 8-wk-old C57BL/6 mice were treated with ACE-031 or vehicle control for 28 days. By the end of treatment, mean body weight of the ACE-031 group was 16% greater than that of the control group, and wet weights of soleus, plantaris, gastrocnemius, and extensor digitorum longus muscles increased by 33, 44, 46 and 26%, respectively (P<0.05). Soleus fiber-type distribution was unchanged with ACE-031 administration, and mean fiber cross-sectional area increased by 22 and 28% (P<0.05) in type I and II fibers, respectively. In the plantaris, a predominantly type II fiber muscle, mean fiber cross-sectional area increased by 57% with ACE-031 treatment. Analysis of myosin heavy chain (MHC) isoform transcripts by real-time PCR indicated no change in transcript levels in the soleus, but a decline in MHC I and IIa in the plantaris. In contrast, electrophoretic separation of total soleus and plantaris protein indicated that there was no change in the proportion of MHC isoforms in either muscle. Thus these data provide optimism that ACE-031 may be a viable therapeutic in the treatment of musculoskeletal diseases. Future studies should be undertaken to confirm that the observed effects are not age dependent or due to the relatively short study duration.


Asunto(s)
Receptores de Activinas Tipo II/administración & dosificación , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Receptores de Activinas Tipo II/genética , Animales , Regulación de la Expresión Génica , Humanos , Hipertrofia , Fragmentos Fc de Inmunoglobulinas/genética , Inmunoglobulina G/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Músculo Esquelético/crecimiento & desarrollo , Músculo Esquelético/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Miostatina/antagonistas & inhibidores , Tamaño de los Órganos , Isoformas de Proteínas , ARN Mensajero/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Factores de Tiempo , Aumento de Peso
13.
Am J Physiol Regul Integr Comp Physiol ; 298(1): R96-R103, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19864340

RESUMEN

Hypoxia, or reduced oxygen, occurs in a variety of clinical and environmental situations. Hypoxic exposure is associated with decreased muscle mass and a concomitant reduction in exercise capacity, although the exact mechanisms are not completely understood. The activin type IIB receptor (ActRIIB) is a receptor for transforming growth factor-beta (TGFbeta) superfamily members that are involved in the negative regulation of lean tissue mass. Given that hypoxia has negative effects on muscle mass and function and that modulation of the ActRIIB has been shown to increase muscle mass, we tested the hypothesis that pharmacological targeting of the ActRIIB for 2 wk would attenuate the loss of muscle mass and function in mice after exposure to normobaric hypoxia. ActRIIB modulation was achieved using a soluble activin receptor/Fc fusion protein (sActRIIB) in mice housed in a hypoxic chamber for 1 or 2 wk. Hypoxia induced a reduction in body weight in PBS- and sActRIIB-treated mice, although sActRIIB-treated mice remained larger throughout the hypoxic exposure. The absolute forces generated by extensor digitorum longus muscles were also significantly greater in sActRIIB- than PBS-treated mice and were more resistant to eccentric contraction-induced force drop after eccentric lengthening contractions. In summary, sActRIIB pretreatment attenuated hypoxia-induced muscle dysfunction. These data suggest that targeting the ActRIIB is an effective strategy to counter hypoxia-induced muscle dysfunction and to preacclimatize to hypoxia in clinical or high-altitude settings.


Asunto(s)
Receptores de Activinas Tipo II/farmacología , Hipoxia/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Esquelético/patología , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Factores de Tiempo
14.
J Comp Neurol ; 514(5): 518-32, 2009 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-19350671

RESUMEN

The central actions of leptin are essential for homeostatic control of adipose tissue mass, glucose metabolism, and many autonomic and neuroendocrine systems. In the brain, leptin acts on numerous different cell types via the long-form leptin receptor (LepRb) to elicit its effects. The precise identification of leptin's cellular targets is fundamental to understanding the mechanism of its pleiotropic central actions. We have systematically characterized LepRb distribution in the mouse brain using in situ hybridization in wildtype mice as well as by EYFP immunoreactivity in a novel LepRb-IRES-Cre EYFP reporter mouse line showing high levels of LepRb mRNA/EYFP coexpression. We found substantial LepRb mRNA and EYFP expression in hypothalamic and extrahypothalamic sites described before, including the dorsomedial nucleus of the hypothalamus, ventral premammillary nucleus, ventral tegmental area, parabrachial nucleus, and the dorsal vagal complex. Expression in insular cortex, lateral septal nucleus, medial preoptic area, rostral linear nucleus, and in the Edinger-Westphal nucleus was also observed and had been previously unreported. The LepRb-IRES-Cre reporter line was used to chemically characterize a population of leptin receptor-expressing neurons in the midbrain. Tyrosine hydroxylase and Cre reporter were found to be coexpressed in the ventral tegmental area and in other midbrain dopaminergic neurons. Lastly, the LepRb-IRES-Cre reporter line was used to map the extent of peripheral leptin sensing by central nervous system (CNS) LepRb neurons. Thus, we provide data supporting the use of the LepRb-IRES-Cre line for the assessment of the anatomic and functional characteristics of neurons expressing leptin receptor.


Asunto(s)
Encéfalo/metabolismo , Leptina/metabolismo , Receptores de Leptina/metabolismo , Animales , Recuento de Células , Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Operón Lac , Masculino , Ratones , Ratones Transgénicos , Fotomicrografía , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Tirosina 3-Monooxigenasa/metabolismo
15.
Exp Neurol ; 217(2): 258-68, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19285073

RESUMEN

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.


Asunto(s)
Receptores de Activinas Tipo II/uso terapéutico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Debilidad Muscular/tratamiento farmacológico , Miostatina/antagonistas & inhibidores , Receptores de Activinas Tipo II/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/fisiopatología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Células CHO , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Transgénicos , Fuerza Muscular/efectos de los fármacos , Fuerza Muscular/fisiología , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/uso terapéutico , Superóxido Dismutasa/genética , Superóxido Dismutasa-1 , Resultado del Tratamiento
16.
J Clin Invest ; 115(12): 3564-72, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16322794

RESUMEN

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.


Asunto(s)
Dieta , Obesidad/genética , Hormonas Peptídicas/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Tejido Adiposo/metabolismo , Alelos , Análisis de Varianza , Alimentación Animal , Animales , Glucemia/metabolismo , Southern Blotting , Western Blotting , Composición Corporal , Peso Corporal , Cruzamientos Genéticos , ADN/metabolismo , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Genotipo , Ghrelina , Heterocigoto , Homeostasis , Hiperglucemia/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Genéticos , Neuronas/metabolismo , Obesidad/metabolismo , Hormonas Peptídicas/química , Fenotipo , ARN Mensajero/metabolismo , Receptores de Ghrelina , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Recombinación Genética , Transducción de Señal , Tinción con Nitrato de Plata , Factores de Tiempo
17.
Peptides ; 26(10): 1728-32, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15993514

RESUMEN

Multiple lines of research provide compelling support for an important role for central serotonergic (5-hydroxytryptamine, 5-HT) and melanocortin pathways in the regulation of food intake and body weight. In this brief review, we outline data supporting a model in which serotonergic pathways affect energy balance, in part, by converging upon central melanocortin systems to stimulate the release of the endogenous melanocortin agonist, alpha-melanocyte stimulating hormone (alpha-MSH). Further, we review the neuroanatomical mapping of a downstream target of alpha-MSH, the melanocortin 4 receptor (MC4R), in the rodent brain. We propose that downstream activation of MC4R-expressing neurons substantially contributes to serotonin's effects on energy homeostasis.


Asunto(s)
Metabolismo Energético/fisiología , Homeostasis/fisiología , Serotonina/fisiología , Transducción de Señal/fisiología , alfa-MSH/fisiología , Animales , Núcleo Arqueado del Hipotálamo/fisiología , Humanos , Leptina/fisiología , Receptor de Melanocortina Tipo 4/fisiología , Receptores de Serotonina/fisiología
18.
Endocrinology ; 146(1): 458-62, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15459118

RESUMEN

In rats, central administration of glucagon-like peptide-1 (GLP-1) elicits symptoms of visceral illness like those caused by the toxin lithium chloride (LiCl), including anorexia, conditioned taste aversion (CTA) formation, and neural activation in the hypothalamus and hindbrain including activation of brainstem preproglucagon cells. Most compellingly, pharmacological antagonists of the GLP-1 receptor (GLP-1R) block several effects of LiCl in rat. The major goal of these experiments was to further test the hypothesis that the central nervous system GLP-1 system is critical to the visceral illness actions of LiCl by using mice with a targeted disruption of the only described GLP-1R. First, we observed that, like the rat, LiCl activates preproglucagon neurons in wild-type mice. Second, GLP-1R -/- mice demonstrated normal anorexic and CTA responses to LiCl. To test the possibility that alternate GLP-1Rs mediate aversive effects, we examined the ability of GLP-1 to produce a CTA in GLP1R -/- mice. Although lateral ventricular GLP-1 produced a CTA in wild-type mice, it did not produce a CTA in GLP-1R -/- mice. Furthermore, the same GLP-1R antagonist that can block the aversive effects of LiCl in the rat failed to do so in the mouse. These results support the conclusion that in mouse, unlike in rat, GLP-1R signaling is not required for the visceral illness response to LiCl. Such species differences are an important consideration when comparing results from rat and mouse studies.


Asunto(s)
Anorexia/inducido químicamente , Reacción de Prevención , Encefalopatías/inducido químicamente , Glucagón/metabolismo , Cloruro de Litio/envenenamiento , Ratones , Fragmentos de Péptidos/metabolismo , Precursores de Proteínas/metabolismo , Gusto/efectos de los fármacos , Animales , Anorexia/metabolismo , Glucagón/antagonistas & inhibidores , Glucagón/farmacología , Péptido 1 Similar al Glucagón , Masculino , Ratones Endogámicos , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Proglucagón , Precursores de Proteínas/antagonistas & inhibidores , Precursores de Proteínas/farmacología , Ratas , Especificidad de la Especie
19.
Nat Med ; 8(3): 262-7, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11875497

RESUMEN

Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.


Asunto(s)
Peso Corporal , Clonación de Organismos , Obesidad/genética , alfa-MSH/análogos & derivados , Tejido Adiposo , Animales , Composición Corporal , Corticosterona/sangre , Cruzamientos Genéticos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Privación de Alimentos , Insulina/sangre , Leptina/sangre , Leptina/farmacología , Masculino , Ratones , Obesidad/fisiopatología , Fenotipo , Embarazo , alfa-MSH/farmacología
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