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FASEB J. 2016 Oct;30(10):3551-3562. Epub 2016 Jul 14.

ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo.

Author information

1
Aix-Marseille Université, Centre National de la Recherche Scientifique, Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Marseille, France.
2
Université de Versailles Saint-Quentin-en-Yvelines, Unités de Formation et de Recherche des Sciences de la Santé, INSERM U1179, Laboratoire International Associé, Biologie Appliquée Handicap Neuromusculaire, Cellules Souches Mésenchymateuses, Saint Quentin en Yvelines Therapeutics, Montigny-le-Bretonneux, France; and Service Génétique Médicale, Centre Hospitalier Universitaire Necker-Enfants Malades, Université Paris Descartes, Paris, France.
3
Aix-Marseille Université, Centre National de la Recherche Scientifique, Centre de Résonance Magnétique Biologique et Médicale, Unité Mixte de Recherche 7339, Marseille, France; benoit.giannesini@univ-amu.fr.

Abstract

Postnatal blockade of the activin type IIB receptor (ActRIIB) represents a promising therapeutic strategy for counteracting dystrophic muscle wasting. However, its impact on muscle function and bioenergetics remains poorly documented in physiologic conditions. We have investigated totally noninvasively the effect of 8-wk administration of either soluble ActRIIB signaling inhibitor (sActRIIB-Fc) or vehicle PBS (control) on gastrocnemius muscle force-generating capacity, energy metabolism, and anatomy in dystrophic mdx mice using magnetic resonance (MR) imaging and dynamic [31P]-MR spectroscopy ([31P]-MRS) in vivo ActRIIB inhibition increased muscle volume (+33%) without changing fiber-type distribution, and increased basal animal oxygen consumption (+22%) and energy expenditure (+23%). During an in vivo standardized fatiguing exercise, maximum and total absolute contractile forces were larger (+40 and 24%, respectively) in sActRIIB-Fc treated animals, whereas specific force-generating capacity and fatigue resistance remained unaffected. Furthermore, sActRIIB-Fc administration did not alter metabolic fluxes, ATP homeostasis, or contractile efficiency during the fatiguing bout of exercise, although it dramatically reduced the intrinsic mitochondrial capacity for producing ATP. Overall, sActRIIB-Fc treatment increased muscle mass and strength without altering the fundamental weakness characteristic of dystrophic mdx muscle. These data support the clinical interest of ActRIIB blockade for reversing dystrophic muscle wasting.-Béchir, N., Pecchi, E., Vilmen, C., Le Fur, Y., Amthor, H., Bernard, M., Bendahan, D., Giannesini, B. ActRIIB blockade increases force-generating capacity and preserves energy supply in exercising mdx mouse muscle in vivo.

KEYWORDS:

Duchenne muscular dystrophy; muscle fatigue; myostatin inhibition; skeletal muscle hypertrophy

PMID:
27416839
DOI:
10.1096/fj.201600271RR
[Indexed for MEDLINE]

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