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Genetics of muscle mass and strength
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Stephen M. Roth, Henning Wackerhage
The researchers used a linkage analysis to further refine the regions identified in their previous studies and so far, have identified the activin receptor 1B (ACVR1B) related to muscle strength (34). Examination of this gene in a transgenic mouse model would be a possible next step to better understand the implications of variation in this gene for muscle traits, but only limited work in this area has been performed to date. This gene is related to the myostatin pathway which we discuss in Chapter 8 as a potential regulator of the adaptation to resistance exercise.
Bone Regeneration Effect of Cassia occidentalis Linn. Extract and Its Isolated Compounds
Published in Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay, Phytochemistry of Plants of Genus Cassia, 2021
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay
Induction of osteoblast differentiation by emodin is associated with the upregulation of BMP-9, osterix, activin receptor-like kinase 1 (ALK1), smad 1, smad 9 and Msh homeobox 2 (Msx2) mRNA levels in osteoblasts. Emodin-induced osteogenic differentiation could be blocked by noggin, thus suggesting the role of BMP-9 as the mediator of this process as BMP-2 expression was unchanged by emodin. In OVX rats, emodin (100 mg/kg, route of administration unspecified) given for 12 weeks although inhibited tartrate-resistant acid phosphatase 5b (TRACP5b, the surrogate of osteoclast number) had no effect on preventing loss of bone volume and strength. A “low dose” E2 (50 μg/kg) also had no effect however, when combined with emodin, complete protection against OVX-induced trabecular osteopenia and loss of strength was observed. As 50 μg/kg E2 had no uterotrophic effect, a combination of low-dose E2 and emodin has been suggested for the treatment of postmenopausal osteoporosis (Chen et al., 2017).
Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Anthony J. Demetris, J.G. Lunz, Vladimir Subbotin, Tong Wu, Isao Nozaki, Sarah Contrucci, Xia Yin
The active form of TGF (beta) binds to the TGFβ receptor II (TβR-II), which dimerizes with and phosphorylates TGF(beta) receptor I (TβR-I). Similarly, activin A binds to the activin receptor II, which dimerizes with activin receptor I. Signal transduction by either of these family members (Fig. 5) is perpetuated by receptor complex phosphorylation of a receptor-regulated SMAD protein (SMAD2 or 3), followed by heterodimerization of the receptor-regulated SMAD with a coSMAD (SMAD4). This complex can then enter the nucleus, where it can interact with a DNA binding partner (DBP) to influence gene transcription. TGF(beta) family members can stimulate transcription of growth inhibitory genes such as p21, or inhibit transcription of growth promoting genes, such as c-myc.165
Pharmacotherapeutic options for cancer cachexia: emerging drugs and recent approvals
Published in Expert Opinion on Pharmacotherapy, 2023
Lorena Garcia-Castillo, Giacomo Rubini, Paola Costelli
Anti-Activin Receptor IIB approaches, including those targeting myostatin, have received quite a lot of attention due to the ability of the underlying signal transduction pathway to work as a negative regulator of muscle mass [56]. In this regard, few trials were performed using anti-myostatin tools such as the monoclonal antibody LY2495655 and the AMG745/Mu-S peptibody. While the latter proved effective in improving lean body mass in prostate cancer patients [57], the former failed to confirm such expectations. Indeed, the trial was interrupted due to significant side effects, in the absence of an appreciable clinical benefit [58]. Finally, a phase II clinical trial (ClinicalTrials.gov Identifier: NCT01433263) tested the effectiveness of Bimagrumab, an anti-Activin Receptor in patients affected by advanced lung or pancreatic cancer, showing improved lean body mass. Despite such controversial results, targeting the Activin Receptor II-dependent pathway remains an attractive option that deserves further investigation.
Current advancements in pharmacotherapy for cancer cachexia
Published in Expert Opinion on Pharmacotherapy, 2023
Guilherme Wesley Peixoto da Fonseca, Ryosuke Sato, Maria Janieire de Nazaré Nunes Alves, Stephan von Haehling
Myostatin, identified in 1997 as a member of the TGF-β superfamily, is secreted primarily from skeletal myocytes and plays a pivotal role as a negative regulator of myogenesis [75]. The binding of myostatin to ActRIIB induces the assembly of type I activin receptor transmembrane kinase 4 or 5 (ALK 4 and ALK 5), subsequently leading to the activation of Smad 2 and Smad 3 complexes. At the same time, activation of ActRIIB leads to the downregulation of Akt, suppressing muscle protein synthesis through the phosphoinositide 3-kinase (PI3-K)/Akt pathway and inducing dephosphorylation of forkhead box 1 (FOXO1). The Smad complexes and FOXO1 subsequently activate the transcription of genes involved in muscle wasting in the nucleus, including E3 ubiquitin ligases such MuRF-1 and MAFbx/atrogin-1, inducing muscle atrophy by the UPS [76].
Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep
Published in Systems Biology in Reproductive Medicine, 2020
Satish Kumar, Pradeep Kumar Rajput, Sangharatna V. Bahire, Basanti Jyotsana, Vijay Kumar, Davendra Kumar
It is well known that the BMP factors (ligands) act through the two sub-types of receptors with serine/threonine kinase activity. Seven type I receptors and five type II serine/threonine kinase receptors have been reported (Attisano and Wrana 1996). Activin receptor-like kinase 1 (Alk1 or ACVRL1), Alk2 (ACVR1), Alk3 (BMPR1A), Alk4 (ACVR1B), Alk5 (TGFβR1), Alk6 (BMPR1B), and Alk7 (ACVR1C) act as type 1 receptors, whereas BMP receptor 2 (BMPRII), Activin receptor 2 (ActR2), Activin receptor 2A/Activin receptor 2B (ActR2A/2B), and TGFβ receptor 2 (TGFβRII) are the type 2 receptors (Kaivo-oja et al. 2006; Loomans and Andl 2016). Out of seven type 1 receptors, three receptors bind and interact with BMP ligands; BMPR1A, BMPR1B, and ActR1A (Horbelt et al. 2012). Out of five type 2 receptors, three receptors are known to interact with BMP ligands; BMPRII, ActR2A, and ActR2B (Wang et al. 2014). These BMP factors interact with hetero-tetrameric complexes of type 1 and type 2 receptors. Type 2 receptor phosphorylates the type 1 receptor. Once phosphorylated, the type 1 receptor phosphorylates one of the receptor-regulated intracellular signaling SMAD proteins (either SMAD1, -5 and -8). Hence, the phosphorylated BMP receptor-regulated SMADs hetero-dimerizes with common SMAD4 and translocate into the nucleus, where these hetero-complexes act as a transcriptional activator to regulate the expression of the target genes (Massagué 1998, 2000; Souza et al. 2004). Interaction of the BMP, TGFβ, and GDF ligands to their respective receptors have been mentioned in Figure 1A-C.