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.
Highlights
Loss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality
REGN1033 and activin receptor IIB (ActRIIB)-hFc were captured through their Fc regions between 32 and 39 resonance unit (RU) by an anti-human Fc antibody immobilized on the sensor chips and were tested for binding to the human myostatin, growth and differentiation factor 11 (GDF11), and activin A
In vitro characterization of REGN1033 anti-myostatin antibody REGN1033 was selected to have high affinity to myostatin (KD = 24 pM) (Table 1). This applies to mouse, rat, monkey, and human since myostatin is 100 % conserved across these species
Summary
Loss 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. Diminished muscle function caused by decreased muscle mass and strength is a key feature of several diseases and disabling conditions and is associated with injury, surgery, frailty, metabolic disorders, and catabolic illnesses such as cancer, heart failure, and chronic lung disease [1, 2]. Myostatin plays a central role in the development and maintenance of skeletal muscle, acting as a negative regulator of muscle mass [4, 5]. Inactivating mutations of the myostatin gene have been described in cattle, sheep, dogs, and humans and result in a profound increase in skeletal muscle mass, without obvious negative
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