Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

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Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease

author Chen, JL
author Walton, KL
author Hagg, A
author Colgan, TD
author Johnson, K
author Qian, H
author Gregorevic, P
author Harrison, CA
Year 2017
citation Proc Natl Acad Sci USA 2017;114(26):E5266-75
issn 0027-8424
URI http://hdl.handle.net/11187/2898
abstract The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (∼20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth. Inhibiting myostatin induced a more profound increase in muscle mass (∼45%), demonstrating a more prominent role for this ligand as a negative regulator of adult muscle mass. Remarkably, codelivery of activin and myostatin inhibitors induced a synergistic response, resulting in muscle mass increasing by as much as 150%. Transcription and protein analysis indicated that this substantial hypertrophy was associated with both the complete inhibition of the Smad2/3 pathway and activation of the parallel bone morphogenetic protein (BMP)/Smad1/5 axis (recently identified as a positive regulator of muscle mass). Analyses indicated that hypertrophy was primarily driven by an increase in protein synthesis, but a reduction in ubiquitin-dependent protein degradation pathways was also observed. In models of muscular dystrophy and cancer cachexia, combined inhibition of activins and myostatin increased mass or prevented muscle wasting, respectively, highlighting the potential therapeutic advantages of specifically targeting multiple Smad2/3-activating ligands in skeletal muscle.
sponsorship NHMRC: 1078907, 1046782, 1077703; Cancer Council Victoria; Endocrine Society Australia; Victorian Cancer Agency
publisher National Academy of Sciences
title Specific targeting of TGF-β family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease
type Journal Article
doi 10.1073/pnas.1620013114
Link https://dx.doi.org/10.1073/pnas.1620013114


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