Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting

Levolger, Stef; Wiemer, Erik A.C.; Vugt, Jeroen L.A. van; Huisman, Sander A.; Vledder, Mark G. van; Engel, Sandra; Ambagtsheer, Gisela; IJzermans, Jan N.M.; Bruin, Ron W. F. de

doi:10.1038/s41598-019-46178-9

Cited by 15 publications

(15 citation statements)

References 69 publications

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“…Some of these in vivo studies reached somewhat contradictory conclusions. In particular, whereas small-molecule inhibitors of ALK4/5 were shown to induce muscle fiber hypertrophy in both wild-type and dystrophic mice ( 48 ) as well as to preserve muscle mass in a cancer cachexia model ( 49 ), delivery of an antisense oligonucleotide directed against Alk4 had the opposite effect, leading to a reduction in muscle mass ( 50 ). Here, we took a genetic approach in which we used the Myl1 -cre transgene to target floxed Alk4 and Alk5 alleles in myofibers.…”

Section: Discussionmentioning

confidence: 99%

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Lee

Lehar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

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Section: Discussionmentioning

confidence: 99%

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Lee

Lehar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, TGF-β-specific inhibition of GW788388 may apply to some pathological conditions. Interestingly, Levolger evaluated the effect of GW788388 on a cancer cachexia model and showed favorable results [ 25 ]. Myostatin or activin, a negative regulator of muscle growth inhibitors, binds to the activin receptor type II receptor, which recruits TβRI, ALK4, or ALK7 [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

Lho

Heo

et al. 2021

IJMS

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We investigated the effectiveness of the transforming growth factor beta-1 (TGF-β) receptor inhibitor GW788388 on the epithelial to mesenchymal transition (EMT) using human peritoneal mesothelial cells (HPMCs) and examined the effectiveness of GW788388 on the peritoneal membrane using a peritoneal fibrosis mouse model. HPMCs were treated with TGF-β with or without GW788388. Animal experiments were conducted on male C57/BL6 mice. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate. GW788388 was administered by once-daily oral gavage. The morphological change, cell migration, and invasion resulted from TGF-β treatment, but these changes were attenuated by cotreatment with GW788388. TGF-β-treated HPMCs decreased the level of the epithelial cell marker and increased the levels of the mesenchymal cell markers. Cotreatment with GW788388 reversed these changes. Phosphorylated Smad2 and Smad3 protein levels were stimulated with TGF-β and the change was attenuated by cotreatment with GW788388. For the peritoneal fibrosis mice, thickness and collagen deposition of parietal peritoneum was increased, but this change was attenuated by cotreatment with GW788388. GW788388, an orally available potent TGF-β receptor type 1 inhibitor, effectively attenuated TGF-β-induced EMT in HPMCs. Cotreatment with GW788388 improved peritoneal thickness and fibrosis, and recovered peritoneal membrane function in a peritoneal fibrosis mouse model.

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“…As an example, recent bimagrumab treatment in older adults with sarcopenia who had six months of adequate nutrition and light exercise was reported to be safe and well-tolerated, increased lean body mass and decreased fat body mass, but did not improve physical function [174]. Lastly, a strategy to systemically block ACVR1 (ALK4/5) receptors by the inhibitor compound GW788388 was also shown to be effective in the preservation of body mass, muscle mass and muscle strength in murine cancer cachexia [175]. Altogether, these observations suggest that blocking ACVRs or their ligands by a variety of methods may represent potentially beneficial therapeutic strategies in cachexia.…”

Section: Effects Of Blocking Acvr2 Signaling On Skeletal Musclementioning

confidence: 99%

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Hulmi

Nissinen

Penna

et al. 2021

Cells

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Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

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Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting

Cited by 15 publications

References 69 publications

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells

Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

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