Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc).
Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc)
Project description:This study was to compare the gene expression of our anti-GDF8 (i.e. anti-myostatin) and anti-activin A antibody combination to that of the activin receptor type IIB (ActRIIB.hFc) trap in SCID mice. The study was conducted in tibialis anterior muscle that is a common muscle type for the hypertrophy study. The combination treatment produces very similar muscle growth in tibialis muscle as the ActRIIB.hFc trap, however our combination blocks two specific ligands compared to the many ligands the receptor trap will inhibit. The difference in gene expression between these groups demonstrates that despite producing similar muscle growth, the trap affecting more genes in muscle without producing additional muscle hypertrophy.
Project description:Recent studies have reported the deleterious physiological and metabolic changes in Mstn-/- mice including impaired force generation and susceptibility to contraction-induced injury. Such observations have raised the concerns about the functional quality of the increased muscle resulting from therapeutic blockade of Mstn. Here we provide proteomic evidence to demonstrate that therapeutic Mstn inhibition has minimal effects on muscle proteome composition whereas the genetic ablation of Mstn induces marked changes. Furthermore, this study also represents the first proteomic analysis of the pharmacological blockage of the Mstn/activin receptor pathway being actively pursued as a potential therapy for multiple muscle wasting disorders.
Project description:Advanced colorectal cancer remains a leading cause of death worldwide and is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ wasting syndrome inclusive of both skeletal and cardiac muscle. Activin receptor type 2B (ACVR2B)-mediated signaling participates in causing skeletal wasting in several disease conditions, and its inhibition restores skeletal muscle mass and prolongs survival in cancer cacehxia. Here we wanted to asses whether ACVR2B antagonism could preserve skeletal and cardiac muscle mass and function in a model of metastatic colorectal cancer.
Project description:TGFβ/Activin subfamilies of ligands. In Drosophila the TGFβ/Activin branch includes three ligands, Myoglianin (Myo), Activin-β (Actβ) and Dawdle (Daw). All three ligands signal through the same type I receptor, Baboon, in conjunction with a type II receptor, Punt or Wit. Baboon has three distinct splice isoforms, termed Babo A, Babo B and Babo C, that differ only in exon 4, which encodes the ligand binding domain. This difference enables each ligand to potentially signal through a single splice isoform39. Formation of the ligand receptor complex stimulates phosphorylation of the receptor-Smad, dSmad2/Smox, which translocates to the nucleus as a complex with the co-Smad Medea where it serves as a transcriptional transducer. In order to gain insight into the genes regulated by Actβ we carried out a transcriptomic analysis comparing Actβ mutants to wild-type controls.
Project description:Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting disorders. Activin type IIB receptor is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of TGF-β family members including myostatin. In order to determine reliable and valid biomarkers for myostatin pathway inhibition, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared to mice genetically lacking myostatin and control mice.
Project description:Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified an increased production and elevated blood levels of soluble pro-cachectic factor Activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Systemic pharmacological blockade of Activin A using soluble activin receptor type IIB ligand trap prevented muscle wasting in a mouse model of experimental CKD.
