Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5266-E5275. doi: 10.1073/pnas.1620013114. Epub 2017 Jun 12.

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

Author information

1
Department of Physiology, Monash University, Clayton, VIC 3800, Australia.
2
Laboratory for Muscle Research and Therapeutic Development, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
3
Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
4
Department of Physiology, University of Melbourne, VIC 3010, Australia.
5
Faculty of Science, Engineering and Technology, Swinburne University of Technology, VIC 3122, Australia.
6
Laboratory for Muscle Research and Therapeutic Development, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; craig.harrison@monash.edu paul.gregorevic@baker.edu.au.
7
Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195.
8
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
9
Department of Physiology, Monash University, Clayton, VIC 3800, Australia; craig.harrison@monash.edu paul.gregorevic@baker.edu.au.

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.

KEYWORDS:

BMP; activin; hypertrophy; muscle; myostatin

PMID:
28607086
PMCID:
PMC5495232
DOI:
10.1073/pnas.1620013114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center