Dataset Information

Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.

ABSTRACT: BACKGROUND:Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization. METHODS:In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. RESULTS:Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. CONCLUSIONS:A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.

SUBMITTER: Rooks DS

PROVIDER: S-EPMC5659065 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.

Rooks Daniel S DS Laurent Didier D Praestgaard Jens J Rasmussen Scott S Bartlett Michael M Tankó László B LB

Journal of cachexia, sarcopenia and muscle 20170914 5

<h4>Background</h4>Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy usi ...[more]

PMID: 28905498

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Project description:Skeletal muscle disuse leads to atrophy, declines in muscle function, and metabolic dysfunction that are often slow to recover. Strategies to mitigate these effects would be clinically relevant. In a double-blind randomized-controlled pilot trial, we examined the safety and tolerability as well as the atrophy mitigating effect of a novel amino acid composition (AXA2678), during single limb immobilization. Twenty healthy young men were randomly assigned (10 per group) to receive AXA2678 or an excipient- and energy-matched non-amino acid containing placebo (PL) for 28d: days 1-7, pre-immobilization; days 8-15, immobilization; and days 16-28 post-immobilization recovery. Muscle biopsies were taken on d1, d8 (immobilization start), d15 (immobilization end), and d28 (post-immobilization recovery). Magnetic resonance imaging (MRI) was utilized to assess quadriceps muscle volume (Mvol), muscle cross-sectional area (CSA), and muscle fat-fraction (FF: the fraction of muscle occupied by fat). Maximal voluntary leg isometric torque was assessed by dynamometry. Administration of AXA2678 attenuated muscle disuse atrophy compared to PL (p < 0.05) with changes from d8 to d15 in PL: ΔMvol = -2.4 ± 2.3% and ΔCSA = -3.1% ± 2.1%, both p < 0.001 vs. zero; against AXA2678: ΔMvol: -0.7 ± 1.8% and ΔCSA: -0.7 ± 2.1%, both p > 0.3 vs. zero; and p < 0.05 between treatment conditions for CSA. During immobilization, muscle FF increased in PL but not in AXA2678 (PL: 12.8 ± 6.1%, AXA2678: 0.4 ± 3.1%; p < 0.05). Immobilization resulted in similar reductions in peak leg isometric torque and change in time-to-peak (TTP) torque in both groups. Recovery (d15-d28) of peak torque and TTP torque was also not different between groups, but showed a trend for better recovery in the AXA2678 group. Thrice daily consumption of AXA2678 for 28d was found to be safe and well-tolerated. Additionally, AXA2678 attenuated atrophy, and attenuated accumulation of fat during short-term disuse. Further investigations on the administration of AXA2678 in conditions of muscle disuse are warranted. Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT03267745.

Project description:Short-term disuse leads to muscle loss driven by lowered daily myofibrillar protein synthesis (MyoPS). However, disuse commonly results from muscle damage, and its influence on muscle deconditioning during disuse is unknown. Twenty-one males [20 ± 1 yr, BMI = 24 ± 1 kg·m-2 (± SE)] underwent 7 days of unilateral leg immobilization immediately preceded by 300 bilateral, maximal, muscle-damaging eccentric quadriceps contractions (DAM; subjects n = 10) or no exercise (CON; subjects n = 11). Participants ingested deuterated water and underwent temporal bilateral thigh MRI scans and vastus lateralis muscle biopsies of immobilized (IMM) and nonimmobilized (N-IMM) legs. N-IMM quadriceps muscle volume remained unchanged throughout both groups. IMM quadriceps muscle volume declined after 2 days by 1.7 ± 0.5% in CON (P = 0.031; and by 1.3 ± 0.6% when corrected to N-IMM; P = 0.06) but did not change in DAM, and declined equivalently in CON [by 6.4 ± 1.1% (5.0 ± 1.6% when corrected to N-IMM)] and DAM [by 2.6 ± 1.8% (4.0 ± 1.9% when corrected to N-IMM)] after 7 days. Immobilization began to decrease MyoPS compared with N-IMM in both groups after 2 days (P = 0.109), albeit with higher MyoPS rates in DAM compared with CON (P = 0.035). Frank suppression of MyoPS was observed between days 2 and 7 in CON (IMM = 1.04 ± 0.12, N-IMM = 1.86 ± 0.10%·day-1; P = 0.002) but not DAM (IMM = 1.49 ± 0.29, N-IMM = 1.90 ± 0.30%·day-1; P > 0.05). Declines in MyoPS and quadriceps volume after 7 days correlated positively in CON (r2 = 0.403; P = 0.035) but negatively in DAM (r2 = 0.483; P = 0.037). Quadriceps strength declined following immobilization in both groups, but to a greater extent in DAM. Prior muscle-damaging eccentric exercise increases MyoPS and prevents loss of quadriceps muscle volume after 2 (but not 7) days of disuse.NEW & NOTEWORTHY We investigated the impact of prior muscle-damaging eccentric exercise on disuse-induced muscle deconditioning. Two and 7 days of muscle disuse per se lowered quadriceps muscle volume in association with lowered daily myofibrillar protein synthesis (MyoPS). Prior eccentric exercise prevented the decline in muscle volume after 2 days and attenuated the decline in MyoPS after 2 and 7 days. These data indicate eccentric exercise increases MyoPS and transiently prevents quadriceps muscle atrophy during muscle disuse.

Project description:BackgroundPoor recovery from periods of disuse accelerates age-related muscle loss, predisposing individuals to the development of secondary adverse health outcomes. Exercise prior to disuse (prehabilitation) may prevent muscle deterioration during subsequent unloading. The present study aimed to investigate the effect of short-term resistance exercise training (RET) prehabilitation on muscle morphology and regulatory mechanisms during 5 days of bed rest in older men.MethodsTen healthy older men aged 65-80 years underwent four bouts of high-volume unilateral leg RET over 7 days prior to 5 days of inpatient bed rest. Physical activity and step-count were monitored over the course of RET prehabilitation and bed rest, whilst dietary intake was recorded throughout. Prior to and following bed rest, quadriceps cross-sectional area (CSA), and hormone/lipid profiles were determined. Serial muscle biopsies and dual-stable isotope tracers were used to determine integrated myofibrillar protein synthesis (iMyoPS) over RET prehabilitation and bed rest phases, and acute postabsorptive and postprandial myofibrillar protein synthesis (aMyoPS) rates at the end of bed rest.ResultsDuring bed rest, daily step-count and light and moderate physical activity time decreased, whilst sedentary time increased when compared with habitual levels (P < 0.001 for all). Dietary protein and fibre intake during bed rest were lower than habitual values (P < 0.01 for both). iMyoPS rates were significantly greater in the exercised leg (EX) compared with the non-exercised control leg (CTL) over prehabilitation (1.76 ± 0.37%/day vs. 1.36 ± 0.18%/day, respectively; P = 0.007). iMyoPS rates decreased similarly in EX and CTL during bed rest (CTL, 1.07 ± 0.22%/day; EX, 1.30 ± 0.38%/day; P = 0.037 and 0.002, respectively). Postprandial aMyoPS rates increased above postabsorptive values in EX only (P = 0.018), with no difference in delta postprandial aMyoPS stimulation between legs. Quadriceps CSA at 40%, 60%, and 80% of muscle length decreased significantly in EX and CTL over bed rest (0.69%, 3.5%, and 2.8%, respectively; P < 0.01 for all), with no differences between legs. No differences in fibre-type CSA were observed between legs or with bed rest. Plasma insulin and serum lipids did not change with bed rest.ConclusionsShort-term resistance exercise prehabilitation augmented iMyoPS rates in older men but did not offset the relative decline in iMyoPS and muscle mass during bed rest.

Dataset Information

Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.

Publications

Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.

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