Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice.

X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by deficiency of the lipid phosphatase, myotubularin. Patients with XLMTM often have severe perinatal weakness that requires mechanical ventilation to prevent death from respiratory failure. Muscle biopsy specimens from patients with XLMTM exhibit small myofibers with central nuclei and central aggregations of organelles in many cells. It was postulated that therapeutically increasing muscle fiber size would cause symptomatic improvement in myotubularin deficiency. Recent studies have elucidated an important role for the activin-receptor type IIB (ActRIIB) in regulation of muscle growth and have demonstrated that ActRIIB inhibition results in significant muscle hypertrophy. To evaluate whether promoting muscle hypertrophy can attenuate symptoms resulting from myotubularin deficiency, the effect of ActRIIB-mFC treatment was determined in myotubularin-deficient (Mtm1δ4) mice. Compared with wild-type mice, untreated Mtm1δ4 mice have decreased body weight, skeletal muscle hypotrophy, and reduced survival. Treatment of Mtm1δ4 mice with ActRIIB-mFC produced a 17% extension of lifespan, with transient increases in weight, forelimb grip strength, and myofiber size. Pathologic analysis of Mtm1δ4 mice during treatment revealed that ActRIIB-mFC produced marked hypertrophy restricted to type 2b myofibers, which suggests that oxidative fibers in Mtm1δ4 animals are incapable of a hypertrophic response in this setting. These results support ActRIIB-mFC as an effective treatment for the weakness observed in myotubularin deficiency.

Design of a Bioreactor to Assess the Effect of Passive Joint Loading in a Live Chick Embryo In Ovo.

There is increasing interest in understanding how mechanical cues (e.g., physical forces due to kicking and other movements) influence the embryological development of tissues and organs. For example, recent studies from our laboratory and others have used the chick embryo model to demonstrate that the compositional and mechanical properties of developing tendons are strongly regulated by embryo movement frequency. However, current research tools for manipulating embryological movements and in ovo (or in utero) mechanical forces are generally limited to chemical treatments that either paralyze or overstimulate muscles without allowing for precise control of physical cues. Thus, in this study, we introduce an instrument that enables application of passive, dynamic ankle flexion at prescribed amplitudes and frequencies in live, developing chick embryos. This device meets the design goals of allowing for precise (<1.5°) control of different waveforms of ankle motion at a physiologically relevant frequency (0.17 Hz) across a range of ankle angles (0-90° plantarflexion) with maintenance of embryo viability comparable to other methods. Impact Statement We describe the design and implementation of a novel bioreactor to precisely control ankle motion in a chick embryo within its physiological environment. The chick embryo has been used for decades to study mechanobiology of musculoskeletal tissue development and regeneration, but approaches have been limited to chemical treatments that either paralyze or overstimulate muscles without allowing for precise control of physical cues. Thus, this novel instrument is a major advancement over current research tools for manipulating chick embryological movements in ovo (or in utero).