ActRIIB blockade increases force‐generating capacity and preserves energy supply in exercisingmdxmouse musclein vivo

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 [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.

Soluble activin receptor type IIB decoy receptor differentially impacts murine osteogenesis imperfecta muscle function

“…58 Unlike MSTN 2/2 mice, Bechir and colleagues found that energy status and function of glycolytic muscles were not disturbed during 6-minute fatigue exercise with ActRIIB blockade in both WT and mdx mice. 44 We examined citrate synthase activity, a measure of mitochondrial content and function, in the mixed Gast muscle and found that it was not altered by sActRIIB-mFc treatment for any genotype studied. This suggests blockade of myostatin via sActRIIB-mFc does not alter this marker of mitochondrial function in Gast muscles.…”

“…A limited group of studies in MSTN −/− mice demonstrated increased force production that was not proportional to their muscle hypertrophy, which may have reflected decreased mitochondrial function, muscle fiber type switching, deficits in oxidative metabolism that can lead to decreased endurance capacity, and/or decreased capillary density in muscle that alters the aerobic metabolism . Unlike MSTN −/− mice, Bechir and colleagues found that energy status and function of glycolytic muscles were not disturbed during 6‐minute fatigue exercise with ActRIIB blockade in both WT and mdx mice . We examined citrate synthase activity, a measure of mitochondrial content and function, in the mixed Gast muscle and found that it was not altered by sActRIIB‐mFc treatment for any genotype studied.…”

“…5). Although other studies of mouse models with muscle atrophy showed that soluble ActRIIB treatment increased absolute muscle contractile function of compromised muscle, 23,24,28,44 there were also reports of earlier muscle fatigability, 26,45 decreased gene expression of components involved in mitochondrial function and oxidative phosphorylation, 46,47 and reduced myofiberspecific function in mdx mice (mouse model of Duchenne muscular dystrophy) with treatment of higher concentrations of soluble ActRIIB. 25 Consistent with these studies, myostatin knockout (MSTN 2/2 ) mice exhibited centralized nuclei, a sign of muscle degeneration, and reduced relative muscle contractile function compared with WT and heterozygous myostatin-deficient (MSTN 1/2 ) littermates, 48 suggesting that a complete absence of myostatin is detrimental to muscle myofiber function.…”

ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass

“…This concurs with our previous observations conducted in vitro using a model of chemotherapy-associated myofiber atrophy 17 . For instance, other reports suggest that the blockade of this signaling pathway mitigates the loss of muscle mass and strength in the presence of muscle atrophy due to cancer 31 , 32 or its treatments 35 , 36 , AIDS 85 , muscular dystrophy 38 , 86 or disuse 78 . ACVR2B/Fc also completely abolished the loss of bone tissue by fully preserving the trabecular bone in the animals exposed to Folfiri, as shown by the μCT analysis.…”

Role of MCT1 and CAII in skeletal muscle pH homeostasis, energetics, and function:in vivoinsights from MCT1 haploinsufficient mice

“…After the whole left lower hindlimb was shaved, electrode cream for electromyography was applied at the knee and heel to optimize electrical stimulation. The anesthetized animal was placed supine within an in‐house–built cradle specially designed for a strictly noninvasive investigation of posterior hindlimb muscle energetics and function (37, 61). The setup integrates an ergometer consisting of a foot pedal coupled to a force transducer and 2 rod‐shaped transcutaneous surface electrodes (one located above the knee and the other under the heel) connected to an electrical stimulator (DS7A; Digitimer, Ltd., Welwyn Springs, United Kingdom).…”