RESUMEN
Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia por Ejercicio/métodos , Sarcopenia/terapia , Nivel de Atención , Accidentes por Caídas/prevención & control , Anciano , Anciano de 80 o más Años , Terapia Combinada , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Vida Independiente , Trastornos de la Destreza Motora/prevención & control , Calidad de Vida , Sarcopenia/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Weakness of urinary sphincter and pelvic floor muscles can cause insufficient urethral closure and lead to stress urinary incontinence. Bimagrumab is a novel myostatin inhibitor that blocks activin type II receptors, inducing skeletal muscle hypertrophy and attenuating muscle weakness. ß2-Adrenergic agonists, such as 5-hydroxybenzothiazolone derivative (5-HOB) and clenbuterol, can enhance muscle growth. We hypothesized that promoting muscle growth would increase leak point pressure (LPP) by facilitating muscle recovery in a dual-injury (DI) stress urinary incontinence model. Rats underwent pudendal nerve crush (PNC) followed by vaginal distension (VD). One week after injury, each rat began subcutaneous (0.3 mL/rat) treatment daily in a blinded fashion with either bimagrumab (DI + Bim), clenbuterol (DI + Clen), 5-HOB (DI + 5-HOB), or PBS (DI + PBS). Sham-injured rats underwent sham PNC + VD and received PBS (sham + PBS). After 2 wk of treatment, rats were anesthetized for LPP and external urethral sphincter electromyography recordings. Hindlimb skeletal muscles and pelvic floor muscles were dissected and stained. At the end of 2 wk of treatment, all three treatment groups had a significant increase in body weight and individual muscle weight compared with both sham-treated and sham-injured rats. LPP in DI + Bim rats was significantly higher than LPP of DI + PBS and DI + Clen rats. There were more consistent urethral striated muscle fibers, elastin fibers in the urethra, and pelvic muscle recovery in DI + Bim rats compared with DI + PBS rats. In conclusion, bimagrumab was the most effective for increasing urethral pressure and continence by promoting injured external urethral sphincter and pelvic floor muscle recovery.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Clenbuterol/uso terapéutico , Incontinencia Urinaria de Esfuerzo/tratamiento farmacológico , Incontinencia Urinaria/tratamiento farmacológico , Agonistas Adrenérgicos beta/uso terapéutico , Animales , Femenino , Músculo Liso , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour-derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL-6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. METHODS: We investigated the interplay between activin A and IL-6 in the cachexia-inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL-6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL-6 from the cancer cells was determined in both culture and tumour-bearing mice by a species-specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy-inducing activities, and muscle mass changes were evaluated in tumour-bearing mice. RESULTS: We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL-6 from cancer cells. By inhibiting activin A signalling, the production of IL-6 from the cancer cells is reduced by 40-50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL-6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non-cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti-activin receptor 2 antibody in cachectic tumour-bearing mice reduces serum levels of cancer cell-derived IL-6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). CONCLUSIONS: Our data support a functional link between activin A and IL-6 signalling pathways and indicate that interference with activin A-induced IL-6 secretion from the tumour has therapeutic potential for cancer-induced cachexia.
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Activinas/metabolismo , Comunicación Autocrina/fisiología , Autofagia/genética , Caquexia/genética , Interleucina-6/metabolismo , Neoplasias Ováricas/genética , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Neoplasias Ováricas/patología , Transducción de SeñalRESUMEN
The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.
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Benzotiazoles/química , Benzotiazoles/farmacología , Sistema Cardiovascular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Receptores Adrenérgicos beta 2/metabolismo , Seguridad , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Anabolizantes/efectos adversos , Anabolizantes/química , Anabolizantes/farmacología , Anabolizantes/uso terapéutico , Animales , Benzotiazoles/efectos adversos , Benzotiazoles/uso terapéutico , Células CHO , Cricetulus , Corazón/efectos de los fármacos , Humanos , Hipertrofia/tratamiento farmacológico , Cinética , Macaca mulatta , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miocitos Cardíacos/efectos de los fármacos , RatasRESUMEN
Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.
Asunto(s)
Receptores de Activinas Tipo II/metabolismo , Envejecimiento/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Miocardio/patología , Transducción de Señal , Activinas/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Animales , Constricción Patológica , Modelos Animales de Enfermedad , Proteínas Relacionadas con la Folistatina/metabolismo , Fragilidad , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Ligandos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Presión , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Ratas , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Índice de Severidad de la Enfermedad , SístoleRESUMEN
RATIONALE: Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators. OBJECTIVES: To assess the effects of bimagrumab on skeletal muscle mass and function in patients with chronic obstructive pulmonary disease (COPD) and reduced skeletal muscle mass. METHODS: Sixty-seven patients with COPD (mean FEV1, 1.05 L [41.6% predicted]; aged 40-80 yr; body mass index < 20 kg/m2 or appendicular skeletal muscle mass index ≤ 7.25 [men] and ≤ 5.67 [women] kg/m2), received two doses of either bimagrumab 30 mg/kg intravenously (n = 33) or placebo (n = 34) (Weeks 0 and 8) over 24 weeks. MEASUREMENTS AND MAIN RESULTS: We assessed changes in thigh muscle volume (cubic centimeters) as the primary endpoint along with 6-minute-walk distance (meters), safety, and tolerability. Fifty-five (82.1%) patients completed the study. Thigh muscle volume increased by Week 4 and remained increased at Week 24 in bimagrumab-treated patients, whereas no changes were observed with placebo (Week 4: +5.9% [SD, 3.4%] vs. 0.0% [3.3%], P < 0.001; Week 8: +7.0% [3.7%] vs. -0.7% [2.8%], P < 0.001; Week 16: +7.8% [5.1%] vs. -0.9% [4.5%], P < 0.001; Week 24: +5.0% [4.9%] vs. -1.3% [4.3%], P < 0.001). Over 24 weeks, 6-minute-walk distance did not increase significantly in either group. Adverse events in the bimagrumab group included muscle-related symptoms, diarrhea, and acne, most of which were mild in severity. CONCLUSIONS: Blocking the action of negative muscle regulators through the activin type II receptors with bimagrumab treatment safely increased skeletal muscle mass but did not improve functional capacity in patients with COPD and low muscle mass. Clinical trial registered with www.clinicaltrials.gov (NCT01669174).
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Receptores de Activinas/antagonistas & inhibidores , Anticuerpos Bloqueadores/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Composición Corporal/efectos de los fármacos , Atrofia Muscular/etiología , Atrofia Muscular/prevención & control , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , MusloRESUMEN
The age-related effects of GDF11 have been a subject of controversy. Here, we find that elevated GDF11 causes signs of cachexia in mice: reduced food intake, body weight, and muscle mass. GDF11 also elicited a significant elevation in plasma Activin A, previously shown to contribute to the loss of skeletal muscle. The effects of GDF11 on skeletal muscle could be reversed by administration of antibodies to the Activin type II receptors. In addition to the effects on muscle, GDF11 increased plasma GDF15, an anorectic agent. The anorexia, but not the muscle loss, could be reversed with a GDF15-neutralizing antibody. GDF15 upregulation is due to GDF11-induced recruitment of SMAD2/3 to the GDF15 promoter. Inhibition of GDF15 can restore appetite but cannot restore the GDF11-induced loss of muscle mass, which requires blockade of ActRII signaling. These findings are relevant for treatment of cachexia.
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Proteínas Morfogenéticas Óseas/metabolismo , Caquexia , Factor 15 de Diferenciación de Crecimiento/biosíntesis , Factores de Diferenciación de Crecimiento/metabolismo , Activinas/metabolismo , Animales , Proteínas Morfogenéticas Óseas/farmacología , Factores de Diferenciación de Crecimiento/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Regulación hacia ArribaRESUMEN
The TGF-ß family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.
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Receptores de Activinas Tipo II/antagonistas & inhibidores , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Hipertrofia/inducido químicamente , Músculo Esquelético/efectos de los fármacos , Receptores de Activinas Tipo II/metabolismo , Activinas/metabolismo , Animales , Anticuerpos Bloqueadores/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Proteínas Morfogenéticas Óseas/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factores de Diferenciación de Crecimiento/metabolismo , Células HEK293 , Humanos , Hipertrofia/patología , Masculino , Ratones , Ratones SCID , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miostatina/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes/metabolismo , Transducción de Señal/efectos de los fármacos , Síndrome Debilitante/tratamiento farmacológico , Síndrome Debilitante/patologíaRESUMEN
OBJECTIVES: To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations. DESIGN: A 24-week, randomized, double-blind, placebo-controlled, parallel-arm, proof-of-concept study. SETTING: Five centers in the United States. PARTICIPANTS: Community-dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women. INTERVENTION: Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21). MEASUREMENTS: Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6-minute walk distance (6MWD). RESULTS: Thirty-two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab-treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 ± 2.19% vs -0.34 ± 2.59%, P < .001; Week 4: 6.12 ± 2.56% vs 0.16 ± 3.42%, P < .001; Week 8: 8.01 ± 3.70% vs 0.35 ± 3.32%, P < .001; Week 16: 7.72 ± 5.31% vs 0.42 ± 5.14%, P < .001; Week 24: 4.80 ± 5.81% vs -1.01 ± 4.43%, P = .002). Participants with slower walking speed at baseline receiving bimagrumab had clinically meaningful and statistically significantly greater improvements in gait speed (mean 0.15 m/s, P = .009) and 6MWD (mean 82 m, P = .022) than those receiving placebo at Week 16. Adverse events in the bimagrumab group included muscle-related symptoms, acne, and diarrhea, most of which were mild in severity and resolved by the end of study. CONCLUSION: Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed.
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Anticuerpos Bloqueadores/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Músculo Esquelético/fisiopatología , Sarcopenia/tratamiento farmacológico , Absorciometría de Fotón , Administración Intravenosa , Anciano , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Femenino , Marcha , Humanos , Masculino , Limitación de la Movilidad , Estados UnidosRESUMEN
BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. RESULTS: Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. CONCLUSIONS: Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients.
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Receptores de Activinas Tipo II/antagonistas & inhibidores , Receptores de Activinas Tipo II/metabolismo , Anticuerpos Bloqueadores/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Caquexia/prevención & control , Neoplasias del Colon/complicaciones , Receptores de Activinas Tipo II/inmunología , Animales , Anticuerpos Monoclonales Humanizados , Peso Corporal/efectos de los fármacos , Caquexia/etiología , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Everolimus/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Serina-Treonina Quinasas TOR/metabolismo , Carga Tumoral/efectos de los fármacosRESUMEN
Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-ß molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.
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Proteínas Morfogenéticas Óseas/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Músculo Esquelético/fisiología , Regeneración , Envejecimiento , Animales , Proteínas Morfogenéticas Óseas/sangre , Proteínas Morfogenéticas Óseas/genética , Diferenciación Celular , Línea Celular , Factores de Diferenciación de Crecimiento/sangre , Factores de Diferenciación de Crecimiento/genética , Humanos , Ratones , Mioblastos/citología , Mioblastos/metabolismo , Miostatina/metabolismo , Ratas , Transducción de Señal , Regulación hacia ArribaRESUMEN
OBJECTIVE: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. METHODS: We measured transforming growth factor ß signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. RESULTS: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. CONCLUSIONS: Transforming growth factor ß superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.
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Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Receptores de Activinas Tipo II/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Bloqueadores , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Método Doble Ciego , Prueba de Esfuerzo , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Enfermedades Neuromusculares/tratamiento farmacológico , Enfermedades Neuromusculares/metabolismo , Enfermedades Neuromusculares/patología , Tamaño de los Órganos , Fosforilación , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Muslo/patología , Resultado del TratamientoRESUMEN
The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
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Receptores de Activinas Tipo II/inmunología , Activinas/metabolismo , Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Hipertrofia/metabolismo , Mioblastos Esqueléticos/metabolismo , Receptores de Activinas Tipo II/metabolismo , Animales , Anticuerpos Bloqueadores/metabolismo , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales Humanizados , Atrofia/inmunología , Atrofia/metabolismo , Diferenciación Celular/fisiología , Humanos , Hipertrofia/patología , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mioblastos Esqueléticos/inmunología , Transducción de Señal/fisiología , Proteína Smad2/metabolismo , Proteína smad3/metabolismoRESUMEN
The marbling of skeletal muscle by ectopic adipose tissue is a hallmark of many muscle diseases, including sarcopenia and muscular dystrophies, and generally associates with impaired muscle regeneration. Although the etiology and the molecular mechanisms of ectopic adipogenesis are poorly understood, fatty regeneration can be modeled in mice using glycerol-induced muscle damage. Using comprehensive molecular and histological profiling, we compared glycerol-induced fatty regeneration to the classical cardiotoxin (CTX)-induced regeneration model previously believed to lack an adipogenic response in muscle. Surprisingly, ectopic adipogenesis was detected in both models, but was stronger and more persistent in response to glycerol. Importantly, extensive differential transcriptomic profiling demonstrated that glycerol induces a stronger inflammatory response and promotes adipogenic regulatory networks while reducing fatty acid ß-oxidation. Altogether, these results provide a comprehensive mapping of gene expression changes during the time course of two muscle regeneration models, and strongly suggest that adipogenic commitment is a hallmark of muscle regeneration, which can lead to ectopic adipocyte accumulation in response to specific physio-pathological challenges.
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Adipocitos/metabolismo , Adipogénesis/genética , Tejido Adiposo/metabolismo , Proteínas Musculares/genética , Debilidad Muscular/genética , Músculo Esquelético/metabolismo , Regeneración/genética , Adipocitos/patología , Tejido Adiposo/patología , Animales , Cardiotoxinas , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica , Glicerol , Metabolismo de los Lípidos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Musculares/metabolismo , Debilidad Muscular/inducido químicamente , Debilidad Muscular/patología , Músculo Esquelético/patologíaRESUMEN
Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.
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Receptores de Activinas Tipo II/antagonistas & inhibidores , Adipogénesis/fisiología , Tejido Adiposo Pardo/metabolismo , Termogénesis/fisiología , Receptores de Activinas Tipo II/inmunología , Receptores de Activinas Tipo II/metabolismo , Adipocitos Marrones/citología , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/ultraestructura , Animales , Anticuerpos Neutralizantes , Diferenciación Celular , Metabolismo Energético , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Miostatina/metabolismo , Transducción de Señal , Proteína smad3/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Skeletal muscle atrophy occurs in a variety of clinical settings, including cachexia, disuse, and denervation. Inflammatory cytokines have been shown to be mediators of cancer cachexia; however, the role of cytokines in denervation- and immobilization-induced skeletal muscle loss remains unknown. In this study, we demonstrate that a single cytokine, TNF-like weak inducer of apoptosis (TWEAK), mediates skeletal muscle atrophy that occurs under denervation conditions. Transgenic expression of TWEAK induces atrophy, fibrosis, fiber-type switching, and the degradation of muscle proteins. Importantly, genetic ablation of TWEAK decreases the loss of muscle proteins and spared fiber cross-sectional area, muscle mass, and strength after denervation. Expression of the TWEAK receptor Fn14 (fibroblast growth factor-inducible receptor 14) and not the cytokine is significantly increased in muscle upon denervation, demonstrating an unexpected inside-out signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor kappaB, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mediator of skeletal muscle atrophy and indicates that the TWEAK-Fn14 system is an important target for preventing skeletal muscle wasting.
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Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Factores de Necrosis Tumoral/metabolismo , Animales , Citocina TWEAK , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Desnervación Muscular , Músculo Esquelético/inervación , Atrofia Muscular/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor de TWEAK , Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/genéticaRESUMEN
During the in vivo maturation of erythrocytes, the number of CR1 per cell decreases by approximately two-thirds in 30 days. The CR1 loss is enhanced in several diseases such as SLE, AIDS, and particularly in factor I deficiency. Microvesicles enriched in CR1 and DAF are released from erythrocytes matured in vitro, leading to the same loss of both molecules. When comparing reticulocytes and erythrocytes, CR1 and DAF were lost similarly in 15 normal individuals, suggesting that vesiculation may be at the origin of CR1 loss in vivo. However, the enhanced loss of CR1 in 3 patients with factor I deficiency was contrasted with a normal loss of DAF, raising the possibility that, in this pathological condition, CR1 might be proteolytically cleaved, leaving small CR1 fragments on the erythrocytes. To answer this question, a rabbit polyclonal antibody was raised against the cytoplasmic (tail) domain of CR1, which recognised specifically CR1 of erythrocytes and urinary vesicles on Western blots. However, no CR1 fragments could be detected on erythrocytes of the factor I deficient patients although this antibody was able to recognise CR1 fragments after treatment of normal erythrocytes or urinary vesicles with elastase. These data suggest that cell surface domains rich in CR1, but not in DAF, are specifically lost in factor I deficiency.