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Inhibition of myostatin (MSTN) and activin signalling by the soluble activin type IIB receptor (ActRIB). MSTN and activin signal to target cells by binding initially to the two activin type II receptors, ActRIIA and/or ActRIIB (also called Acvr2 and Acvr2b, respectively) and then to the type I receptors, ALK4 and/or ALK5. The activated type I receptors phosphorylate the intracellular mediators of signalling, Smad2 and/or Smad3. Signalling through this pathway results in the inhibition of muscle differentiation and growth. The activities of MSTN and activin are regulated normally by a number of different extracellular binding proteins, such as follistatin and FSTL-3. The soluble form of ActRIIB (ActRIIB/Fc) can act as a ligand trap by binding MSTN and activin and preventing the ligands from binding to their true receptors.
Source publication
Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathways - in an attempt to fight the...
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Myostatin is an extracellular cytokine mostly expressed in skeletal muscles and known to play a crucial role in the negative regulation of muscle mass. Upon the binding to activin type IIB receptor, myostatin can initiate several different signalling cascades resulting in the upregulation of the atrogenes and downregulation of the important for myo...
Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively impacts quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including pro-inflammatory cy...
Myostatin, a member of the transforming growth factor (TGF)-β family of secreted ligands, is a strong negative regulator of muscle growth. As such, therapeutic inhibitors of myostatin are actively being investigated for their potential in the treatment of muscle-wasting diseases such as muscular dystrophy and sarcopenia. Here, we sought to develop...
Citations
... Maintaining myofiber size is essential for proper muscle function. Muscle atrophy characterizes aging, disuse, cancer cachexia, and disease [1][2][3]. Notably, individual muscles and myofiber types are differentially affected in many of these settings [4]. For example, in humans, the soleus muscle is largely spared from sarcopenia, while other lower limb muscles are reduced in size [5]. ...
Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13395-023-00329-9.
... Myostatin is a member of the tumor growth factor β (TGF-β) family and is known as growth/differentiation factor 8 (GDF-8) (McPherron et al., 1997;Lee and McPherron, 2001). In the myostatin (MSTN) signaling pathway, MSTN binds to its receptors ActIIA/ActIIB and activates ALK4 and ALK5 that phosphorylate Smad2/3, leading to its binding with Smad4 and translocation of the complex to the nucleus, and where it blocks the transcription of genes responsible for myogenesis (Lee et al., 2005;Elkina et al., 2011;Han and Mitch, 2011;Lee and Glass, 2011;Lassiter et al., 2019). Myostatin is solely expressed in skeletal muscle during embryogenesis to control the differentiation and proliferation of the myoblasts (McPherron et al., 1997). ...
Background: Muscle development, egg production, and plumage colors are different between native and broiler chickens. The study was designed to investigate why improved Aseel (PD4) is colorful, stronger, and grew slowly compared with the control broiler (CB).
Methods: A microarray was conducted using the 7th-day embryo (7EB) and 18th-day thigh muscle (18TM) of improved Aseel and broiler, respectively. Also, we have selected 24 Gallus gallus candidate reference genes from NCBI, and total RNA was isolated from the broiler, improved Aseel embryo tissues, and their expression profiles were studied by real-time quantitative PCR (qPCR). Furthermore, microarray data were validated with qPCR using improved Aseel and broiler embryo tissues.
Results: In the differential transcripts screening, all the transcripts obtained by microarray of slow and fast growth groups were screened by fold change ≥ 1 and false discovery rate (FDR) ≤ 0.05. In total, 8,069 transcripts were differentially expressed between the 7EB and 18TM of PD4 compared to the CB. A further analysis showed that a high number of transcripts are differentially regulated in the 7EB of PD4 (6,896) and fewer transcripts are differentially regulated (1,173) in the 18TM of PD4 compared to the CB. On the 7th⁻ and 18th-day PD4 embryos, 3,890, 3,006, 745, and 428 transcripts were up- and downregulated, respectively. The commonly up- and downregulated transcripts are 91 and 44 between the 7th- and 18th-day of embryos. In addition, the best housekeeping gene was identified. Furthermore, we validated the differentially expressed genes (DEGs) related to muscle growth, myostatin signaling and development, and fatty acid metabolism genes in PD4 and CB embryo tissues by qPCR, and the results correlated with microarray expression data.
Conclusion: Our study identified DEGs that regulate the myostatin signaling and differentiation pathway; glycolysis and gluconeogenesis; fatty acid metabolism; Jak-STAT, mTOR, and TGF-β signaling pathways; tryptophan metabolism; and PI3K-Akt signaling pathways in PD4. The results revealed that the gene expression architecture is present in the improved Aseel exhibiting embryo growth that will help improve muscle development, differentiation, egg production, protein synthesis, and plumage formation in PD4 native chickens. Our findings may be used as a model for improving the growth in Aseel as well as optimizing the growth in the broiler.
... Loss of muscle mass accounts for the bulk of the body weight loss, which is a powerful and independent predictor of poor survival in PC [6]. Ameliorating muscle wasting could significantly improve cancer survival [7]. However, an understanding of the highly complex etiology of PC-induced muscle wasting remains limited. ...
Pancreatic cancer (PC) patients are highly prone to cachexia, a lethal wasting syndrome featuring muscle wasting with an undefined etiology. Recent data indicate that certain murine cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 through extracellular vesicles (EVs) to activate p38β MAPK-mediated catabolic pathways primarily through Toll-like receptor 4 (TLR4). However, whether human PC induces cachexia through releasing Hsp70 and Hsp90 is undetermined. Here, we investigated whether patient-derived PC cells induce muscle cell atrophy directly through this mechanism. We compared cancer cells isolated from patient-derived xenografts (PDX) from three PC patients who had cachexia (PCC) with those of three early-stage lung cancer patients without cachexia (LCC) and two renal cancer patients who were not prone to cachexia (RCC). We observed small increases of Hsp70 and Hsp90 released by LCC and RCC in comparison to non-cancer control cells (NCC). However, PCC released markedly higher levels of Hsp70 and Hsp90 (~ 6-fold on average) than LCC and RCC. In addition, PCC released similarly increased levels of Hsp70/90-containing EVs. In contrast to RCC and LCC, PCC-conditioned media induced a potent catabolic response in C2C12 myotubes including the activation of p38 MAPK and transcription factor C/EBPβ, upregulation of E3 ligases UBR2 and MAFbx, and increase of autophagy marker LC3-II, resulting in the loss of the myosin heavy chain (MHC ~50%) and myotube diameter (~60%). Importantly, the catabolic response was attenuated by Hsp70- and Hsp90-neutralizing antibodies in a dose-dependent manner. These data suggest that human PC cells release high levels of Hsp70 and Hsp90 that induce muscle atrophy through a direct action on muscle cells.
... Myostatin is a member of tumor growth factor β (TGF-β) and is known as growth/differentiation factor 8 (GDF-8) [101,102]. In the myostatin (MSTN) signaling pathway, MSTN binds to its receptors ActIIA/ActIIB and activates ALK4 and ALK5 that phosphorylate Smad2/3 leads to its binding with Smad4 and translocation of the complex to the nucleus and where it blocks the transcription of genes responsible for the myogenesis [103,104,105,106,107] (Fig. 8). The myostatin is solely expressed in skeletal muscle during embryogenesis to control the differentiation and proliferation of the myoblasts [101]. ...
Background: Chicken is one of the important meat sources throughout the globe. Muscle development and egg production are important genetic traits in commercially raising chickens. However, not much information is available in the fast and slow growth of chicken to determine the expression of genes involved in muscle development and egg production in embryo initiation and developmental stages. This study was designed to investigate why improved Aseel (PD4) growing slowly compared with the control broiler (CB), microarray was conducted with the 7th-day embryo and 18th-day thigh muscle of improved Aseel (PD4) and control broiler (CL), respectively.
Results: In the differential transcripts screening, all the transcripts obtained by microarray of slow and fast growth groups were screened by fold change ≥1 and false discovery rate (FDR) <0.05. In total, 19022 transcripts were differentially expressed between the 7th-day embryo and 18th-day thigh muscle of improved Aseel compared to the control broiler. Further analysis showed that a high number of transcripts are differentially regulated in the 7th-day improved Aseel embryo (15382) and fewer transcripts were differentially regulated (3640) in the 18th-day thigh muscle of improved Aseel compared to control broiler. In the 7th and 18th-day improved Aseel embryo, 10127, 2102, 5255, and 1538 transcripts were up and down-regulated, respectively. The commonly up and down-regulated transcripts are 545 and 381 between the 7th and 18th-day of embryos. In this study, we have selected 18 Gallus gallus candidate reference genes from NCBI and total RNA was isolated from control broiler, improved Aseel embryo tissues, and studied their expression profiles by real-time quantitative PCR (qPCR). The best housekeeping gene was identified by using geNorm, NormFinder, BestKeeper, Delta CT, and RefFinder analytical software. The result showed that the TFRC gene is the most stable and further it is used for qPCR data normalization. Further, to validate the differentially expressed genes (DEGs) related to muscle growth, myostatin signaling and development, fatty acid metabolism genes in improved Aseel (PD4) and control broiler embryo tissues by qPCR.
Conclusion: Our study identified DEGs that regulate myostatin signaling and differentiation pathway, glycolysis and gluconeogenesis, fatty acid metabolism, Jak-STAT, mTOR, and TGF-β signaling pathways, tryptophan metabolism, PI3K-Akt signaling pathways in improved Aseel. The results revealed that the gene expression architecture is present in the improved Aseel exhibiting embryo growth that will help to improve muscle development, differentiation, egg production, as well as protein synthesis in improved Aseel native chicken. Our findings may be used as a model for improving the growth in improved Aseel as well as optimizing the growth in the control broiler.
... Similarly, antitumor treatment, including surgery, chemotherapy, or radiotherapy, may cause nau-sea, vomiting, and anorexia to varying degrees, resulting in oxidative stress response and gastrointestinal dysfunction in cancer patients (de van der Schueren et al., 2018). These consequences can lead to a decrease in the intake and absorption of nutrients, and further result in malnutrition (Lee & Glass, 2011). ...
To improve the difficulties related to malnutrition, nutritional support has become an essential part of multidisciplinary comprehensive treatment for cancer. Lipids are essential nutrient source for the human body, and nowadays in clinical practices, it has a positive interventional effect on patients suffering from cancer. However, contribution of lipids in nutritional support of cancer patients is still poorly understood. Moreover, the sensory and physicochemical properties of lipids can severely restrict their applications in lipid‐rich formula foods. In this review article, for the first time, we have presented a summary of the existing studies which were related to the associations between different lipids and improved malnutrition in cancer patients and discussed possible mechanisms. Subsequently, we discussed the challenges and effective solutions during processing of lipids into formula foods. Further, by considering existing problems in current lipid nutritional support, we proposed a novel method for the treatment of malnutrition, including developing individualized lipid nutrition for different patients depending on the individual's genotype and enterotype. Nonetheless, this review study provides a new direction for future research on nutritional support and the development of lipid‐rich formula foods for cancer patients, and probably will help to improve the efficacy of lipids in the treatment of cancer malnutrition.
... CAC creates an additional burden to caregivers due to the inability to reverse it with nutritional support alone. This problem remains a major issue in cancer treatment, and currently there are no management strategies that address this phenomenon [3,4]. ...
Cancer-associated cachexia is a wasting syndrome that affects up to 50% of cancer patients. It is defined as unintentional weight loss ≥5% over 6 months and characterized by muscle atrophy, fatigue, and anorexia that are refractory to nutritional support. Sarcoma describes a diverse group of malignancies arising from the connective tissues. Sarcoma patients are uniquely susceptible to cancer-associated cachexia given its origins in the musculoskeletal system. Our previous research suggests that sarcoma cells may contribute to sarcoma-associated cachexia (SAC) via establishment of TNF-α-mediated inflammation and dysregulation of muscle homeostasis by abnormal Notch signaling. Here, we examine the role of the Notch pathway and pro-inflammatory cytokines in cells derived from cachectic and non-cachectic human sarcoma patients. We observed increased expression of Notch pathway genes in the cachexia group while no differences in pro-inflammatory cytokines were observed. Co-culture of muscle-derived stem cells (MDSCs) and sarcoma cells demonstrated the inhibition of MDSC maturation with both cachectic and non-cachectic patient cells, corresponding to elevated Pax7 and Notch pathway expression in MDSCs. Our findings suggest that there is no difference in inflammatory profile between cachexia and non-cachexia sarcoma samples. However, Cachectic sarcoma samples express increased Notch that mediates muscle wasting possibly through inhibition of myogenesis.
... In the MSTN signaling pathway, MSTN binds to its receptors, ActIIA or ActIIB that activate ALK4 and ALK5 that in turn phosphorylate Smad 2 and 3 that translocate to the nucleus to initiate changes in transcription of downstream genes; FSTN functions to inhibit and limit MSTN activity (Han and Mitch, 2011;Lee and Glass, 2011). In the present study, expression of the inhibitory gene MSTN (a member of the TGF-β family), one of its receptors (ActRIIB), and two transcription factors of MSTN signaling, SMAD2 and SMAD3, were upregulated in the low FE compared to high FE breast muscle but there were no differences in FSTN, the ActRIIA, ALK4 and ALK5 expression (Figure 2). ...
... Thus, differences in FE in the PedM broiler line in this study could be due in part to different haplotypes of the MSTN gene. Figure 3 (adapted from Lee and Glass, 2011), summarizes the initial steps in the MSTN signaling pathway in the present study that would potentially exert a negative effect on muscle hypertrophy and differentiation in the low FE phenotype. ...
... Gene expression of the molecules shown in green were downregulated in the high FE phenotype (upregulated in the low FE phenotype) whereas molecules in gray were not differentially expressed between the groups. The figure is adapted from Lee and Glass (2011). ...
Background: Feed efficiency (FE, gain to feed) is an important genetic trait as 70% of the cost of raising animals is due to feed costs. The objective of this study was to determine mRNA expression of genes involved in muscle development and hypertrophy, and the insulin receptor-signaling pathway in breast muscle associated with the phenotypic expression of FE.
Methods: Breast muscle samples were obtained from Pedigree Male (PedM) broilers (8 to 10 week old) that had been individually phenotyped for FE between 6 and 7 week of age. The high FE group gained more weight but consumed the same amount of feed compared to the low FE group. Total RNA was extracted from breast muscle (n = 6 per group) and mRNA expression of target genes was determined by real-time quantitative PCR.
Results: Targeted gene expression analysis in breast muscle of the high FE phenotype revealed that muscle development may be fostered in the high FE PedM phenotype by down-regulation several components of the myostatin signaling pathway genes combined with upregulation of genes that enhance muscle formation and growth. There was also evidence of genetic architecture that would foster muscle protein synthesis in the high FE phenotype. A clear indication of differences in insulin signaling between high and low FE phenotypes was not apparent in this study.
Conclusion: These findings indicate that a gene expression architecture is present in breast muscle of PedM broilers exhibiting high FE that would support enhanced muscle development-differentiation as well as protein synthesis compared to PedM broilers exhibiting low FE.
... The FDA-informed analysis plan described that LBM, measured at day 84, equal to or higher than the initial LBM of patients is translated into response to treatment [73], citing that "prevention is important, as muscle wasting begins before outward clinical signs or symptoms, including overt weight loss" [76]. However, whether physical function tests (e.g., handgrip strength, sit-to-stand, stair-climbing power) are suitable surrogate measures of strength in patients with advanced cancer and cachexia still needs to be established [77]. ...
Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia.
... Activin/follistatin (FST)/myostatin-signaling has been identified as an important pathway involved in muscle metabolism, differentiation, and growth (6,7). Binding of activins (activin A and activin B) as well as of (the highly homologous to activins) myostatin to activin receptors type II (ActRII) activates a signaling cascade resulting in the inhibition of muscle growth and differentiation (8). ...
... Myostatin is primarily secreted by muscle tissue, and most previous reports have shown a repression of the myostatin gene in muscle during exercise. However, other studies, including one from our group, did not observe a similar reduction of circulating myostatin during exercise (7,17,(27)(28)(29)(30)(31)(32)(33). Limitations of our study include the lack of muscle biopsies to evaluate ActRII expression or the myostatin signaling cascade, which would make the study more invasive, the recruitment of male participants only, and the relatively small, albeit adequately powered, sample size of study 2. ...
Context
Clinical trials are evaluating the efficacy of inhibitors of the myostatin pathway in neuromuscular and metabolic diseases. Activins and follistatins are major regulators of the myostatin pathway, but their physiology in relation to metabolic and anthropometric variables and in response to exercise remains to be fully elucidated in humans.
Objective
We investigated whether concentrations of circulating activin A, activin B, follistatin and follistatin-like 3 (FSTL3) are associated with anthropometric and metabolic variables and whether they are affected by exercise.
Design
Activin A, activin B, follistatin and FSTL3 were measured in a) 80 subjects divided according to age (young vs old) and fitness status (active vs sedentary) before and after exercise at 70% VO2max, followed by 90% of VO2max until exhaustion, b) 23 subjects (9 healthy and 14 with metabolic syndrome [MetS]) that completed four sessions: no exercise, high-intensity interval exercise, continuous moderate-intensity exercise, and resistance exercise for up to 45 min.
Results
At baseline, follistatin and FSTL3 concentrations were positively associated with age, fat percentage, and BMI (p<0.001). Follistatin was positively associated with serum cholesterol (p=0.005), LDL-cholesterol (p=0.01), triglycerides (p=0.033) and blood pressure (p=0.019), while activin A and activin B were higher in physically active participants (p=0.056 and 0.029, respectively). All exercise types increased the levels of all hormones about 10-21% (p=0.034 for activin B, p<0.001 for the others) independently of the presence of MetS.
Conclusion
Concentrations of circulating activins and follistatins are associated with metabolic parameters and increase after 45 min of exercise.
... 1,2 Skeletal muscle has been an underappreciated tissue in health and disease, 3 but a growing body of evidence suggests a beneficial role for treating muscle tissue in cachectic conditions associated with different diseases, such as cancer. 4 Muscle wasting in cancer cachexia is a consequence of decreased muscle protein synthesis, 5,6 impaired regeneration 7 and/or increased protein degradation, 6 but their relative importance and mechanisms are not well known. One possible mechanism for muscle wasting in cachexia is increased signalling through activin receptor ligands, such as myostatin and activins. ...
... 9,14,16 These findings together with results from treatments affecting other pathways [19][20][21][22] as well as epidemiological evidence in humans 2 have led to suggestions for a possible causal link between preservation of muscle mass and improved survival. 4 This hypothesis is in part supported by the present study showing that increasing muscle mass and maintaining it by continued blocking of ACVR2B ligands improves survival. In comparison, the discontinuation of the treatment before the tumour formation led to a systematically worse outcome and also shorter survival. ...
Background
Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered.
Methods
The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non‐muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B‐Fc). Treatment with sACVR2B‐Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non‐muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking.
Results
Blocking of ACVR2 ligands improved survival in tumour‐bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro‐inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B‐Fc was not explained by decreased markers of myeloid‐derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late‐endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis.
Conclusions
The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non‐muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late‐endosomes in cancer opens up new research questions and possible treatment options for cachexia.
