Myostatin/activin blocking combined with exercise reconditions skeletal muscle expression profile of mdx mice

Heikki Kainulainen; Konstantinos G Papaioannou; Mika Silvennoinen; Reija Autio; Janne Saarela; Bernardo M Oliveira; Miro Nyqvist; Arja Pasternack; Peter A C 't Hoen; Urho M Kujala; Olli Ritvos; Juha J Hulmi

doi:10.1016/j.mce.2014.10.001

Myostatin/activin blocking combined with exercise reconditions skeletal muscle expression profile of mdx mice

Mol Cell Endocrinol. 2015 Jan 5:399:131-42. doi: 10.1016/j.mce.2014.10.001. Epub 2014 Oct 7.

Affiliations

¹ Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Rautpohjankatu 8, P.O. Box 35, Jyväskylä FI-40014, Finland.
² Department of Signal Processing, Tampere University of Technology, Korkeakoulunkatu 1, P.O. BOX 553, Tampere FI-33101, Finland.
³ Department of Medical Biochemistry and Genetics, University of Turku, Kiinamyllynkatu 10, Turku FIN-20520, Finland.
⁴ Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, P.O. Box 21, Helsinki FIN-00014, Finland.
⁵ Department of Human Genetics, Leiden University Medical Center (LUMC), Postzone S-04-P, PO Box 9600, Leiden 2300 RC, The Netherlands.
⁶ Department of Health Sciences, University of Jyväskylä, Rautpohjankatu 8, P.O. Box 35, Jyväskylä FI-40014, Finland.
⁷ Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Rautpohjankatu 8, P.O. Box 35, Jyväskylä FI-40014, Finland. Electronic address: [email protected].

PMID: 25304272
DOI: 10.1016/j.mce.2014.10.001

Abstract

Duchenne muscular dystrophy is characterized by muscle wasting and decreased aerobic metabolism. Exercise and blocking of myostatin/activin signaling may independently or combined counteract muscle wasting and dystrophies. The effects of myostatin/activin blocking using soluble activin receptor-Fc (sActRIIB-Fc) administration and wheel running were tested alone or in combination for 7 weeks in dystrophic mdx mice. Expression microarray analysis revealed decreased aerobic metabolism in the gastrocnemius muscle of mdx mice compared to healthy mice. This was not due to reduced home-cage physical activity, and was further downregulated upon sActRIIB-Fc treatment in enlarged muscles. However, exercise activated pathways of aerobic metabolism and counteracted the negative effects of sActRIIB-Fc. Exercise and sActRIIB-Fc synergistically increased expression of major urinary protein, but exercise blocked sActRIIB-Fc induced phosphorylation of STAT5 in gastrocnemius muscle. In conclusion, exercise alone or in combination with myostatin/activin blocking corrects aerobic gene expression profiles of dystrophic muscle toward healthy wild type mice profiles.

Keywords: Muscle hypertrophy; Muscular dystrophy; Oxidative metabolism; Physical activity; mRNA profiling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type II / genetics
Activin Receptors, Type II / pharmacology*
Animals
Inhibin-beta Subunits / antagonists & inhibitors*
Inhibin-beta Subunits / metabolism
Mice
Mice, Inbred mdx
Muscle, Skeletal / metabolism*
Myostatin / antagonists & inhibitors*
Myostatin / metabolism
Phosphorylation / drug effects
Physical Conditioning, Animal*
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / pharmacology
STAT5 Transcription Factor / metabolism

Substances

Mstn protein, mouse
Myostatin
Recombinant Fusion Proteins
STAT5 Transcription Factor
inhibin beta A subunit
Inhibin-beta Subunits
Activin Receptors, Type II
activin receptor type II-B