-Because it leads to a rapid and massive muscle hypertrophy, postnatal blockade of the activin type IIB receptor (ActRIIB) is a promising therapeutic strategy for counteracting muscle wasting. However, the functional consequences remain very poorly documented in vivo. Here, we have investigated the impact of 8-wk ActRIIB blockade with soluble receptor (sActRIIB-Fc) on gastrocnemius muscle anatomy, energy metabolism, and force-generating capacity in wild-type mice, using totally noninvasive magnetic resonance imaging (MRI) and dynamic 31 P-MRS. Compared with vehicle (PBS) control, sActRIIB-Fc treatment resulted in a dramatic increase in body weight (ϩ29%) and muscle volume (ϩ58%) calculated from hindlimb MR imaging, but did not alter fiber type distribution determined via myosin heavy chain isoform analysis. In resting muscle, sActRIIB-Fc treatment induced acidosis and PCr depletion, thereby suggesting reduced tissue oxygenation. During an in vivo fatiguing exercise (6-min repeated maximal isometric contraction electrically induced at 1.7 Hz), maximal and total absolute forces were larger in sActRIIB-Fc treated animals (ϩ26 and ϩ12%, respectively), whereas specific force and fatigue resistance were lower (Ϫ30 and Ϫ37%, respectively). Treatment with sActRIIB-Fc further decreased the maximal rate of oxidative ATP synthesis (Ϫ42%) and the oxidative capacity (Ϫ34%), but did not alter the bioenergetics status in contracting muscle. Our findings demonstrate in vivo that sActRIIB-Fc treatment increases absolute force-generating capacity and reduces mitochondrial function in glycolytic gastrocnemius muscle, but this reduction does not compromise energy status during sustained activity. Overall, these data support the clinical interest of postnatal ActRIIB blockade. skeletal muscle hypertrophy; activin type IIB receptor; myostatin; force; fatigue ACTIVIN TYPE IIB RECEPTOR (ActRIIB) is a transmembrane serinethreonine kinase receptor highly expressed in mammalian skeletal muscle. It mediates signaling for myostatin (GDF8) and other members of the transforming growth factor-␤ family that are involved in the negative regulation of skeletal muscle development (16,37). Disruption of the ActRIIB signaling pathway leads to a rapid and massive increase in muscle mass resulting from fiber hypertrophy with increased myofiber protein synthesis (10, 58). In that context, several pharmacological approaches based on the postnatal ActRIIB signaling blockade have been considered for counteracting muscle wasting commonly associated to aging, neuromuscular disorders and various catabolic diseases (17,33,38). These approaches mainly include the systemic delivery of neutralizing antibodies against ActRIIB or myostatin (31, 36), and injection of a soluble recombinant form of ActRIIB (sActRIIB-Fc), which acts as a decoy receptor disrupting the interaction of endogenous ActRIIB receptor with its ligands (5,38,44).Although ActRIIB signaling blockade has been already tested in patients (30, 57) and animal models (10,44,47) suffering from dystrophi...

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 [P]-MR spectroscopy ([P]-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.