Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice

Abstract

BackgroundLoss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality. The role of myostatin as a key negative regulator of skeletal muscle mass and function has supported the concept that inactivation of myostatin could be a useful approach for treating muscle wasting diseases.MethodsWe generated a myostatin monoclonal blocking antibody (REGN1033) and characterized its effects in vitro using surface plasmon resonance biacore and cell-based Smad2/3 signaling assays. REGN1033 was tested in mice for the ability to induce skeletal muscle hypertrophy and prevent atrophy induced by immobilization, hindlimb suspension, or dexamethasone. The effect of REGN1033 on exercise training was tested in aged mice. Messenger RNA sequencing, immunohistochemistry, and ex vivo force measurements were performed on skeletal muscle samples from REGN1033-treated mice.ResultsThe human monoclonal antibody REGN1033 is a specific and potent myostatin antagonist. Chronic treatment of mice with REGN1033 increased muscle fiber size, muscle mass, and force production. REGN1033 prevented the loss of muscle mass induced by immobilization, glucocorticoid treatment, or hindlimb unweighting and increased the gain of muscle mass during recovery from pre-existing atrophy. In aged mice, REGN1033 increased muscle mass and strength and improved physical performance during treadmill exercise.ConclusionsWe show that specific myostatin antagonism with the human antibody REGN1033 enhanced muscle mass and function in young and aged mice and had beneficial effects in models of skeletal muscle atrophy.

Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice

“…The authors used either recombinant myostatin antibodies,32, 33 myostatin propeptides,34, 35 myostatin antagonists,36, 37 or soluble myostatin receptors 38 . By targeting myostatin at the protein level, the effects from these strategies were immediate and generally more efficient than using antisense therapies to disrupt myostatin pre-mRNA 46 .…”

“…Myostatin downregulation has been reported to increase muscle mass and muscle strength in an mdx mouse model of DMD through the use of myostatin-blocking agents like monoclonal antibodies,32, 33 recombinant myostatin propeptides,34, 35 myostatin antagonists,36, 37 or soluble myostatin receptors 38 . We and others have demonstrated that it is possible to employ antisense therapy inducing destructive exon skipping of myostatin pre-mRNA for inhibiting myostatin expression.…”

Cytokine Signaling in Skeletal Muscle Wasting

“…Upregulation of myostatin has been reported in several muscle wasting conditions [67,68]. Chronic treatment of mice with a human monoclonal antibody (REGN1033) that blocks myostatin increased muscle mass and force production, and prevented the loss of muscle mass in several muscle wasting models including immobilization and dexamethasone treatment [68]. In aged mice, REGN1033 improved muscle function during treadmill exercise [68].…”

“…Chronic treatment of mice with a human monoclonal antibody (REGN1033) that blocks myostatin increased muscle mass and force production, and prevented the loss of muscle mass in several muscle wasting models including immobilization and dexamethasone treatment [68]. In aged mice, REGN1033 improved muscle function during treadmill exercise [68]. Although untested, REGN1033 might be beneficial for the elderly, because, at least in old rats, exercise alone was not able to reduce TNF-/ level [69].…”

Activin A more prominently regulates muscle mass in primates than does GDF8

“…In addition, we used REGN2477 in combination with REGN1033, an anti-GDF8 monoclonal antibody7. We show that antibody-mediated inhibition of GDF8 and activin A leads to a strong and synergistic increase in muscle mass in mice and monkeys similar to that induced by treatment with ActRIIB.hFc.…”