SUMMARY Age-related frailty may be due to decreased skeletal muscle regeneration. The role of TGF-β molecules myostatin and GDF11 in regeneration is unclear. Recent studies showed an age-related decrease in GDF11 and that GDF11 treatment improves muscle regeneration, which were contrary to prior studies. We now show that these recent claims are not reproducible and the reagents previously used to detect GDF11 are not GDF11 specific. We develop a GDF11-specific immunoassay and show a trend toward increased GDF11 levels in sera of aged rats and humans. GDF11 mRNA increases in rat muscle with age. Mechanistically, GDF11 and myostatin both induce SMAD2/3 phosphorylation, inhibit myoblast differentiation, and regulate identical downstream signaling. GDF11 significantly inhibited muscle regeneration and decreased satellite cell expansion in mice. Given early data in humans showing a trend for an age-related increase, GDF11 could be a target for pharmacologic blockade to treat age-related sarcopenia.
The TNF-related cytokine TWEAK promotes skeletal muscle atrophy that is associated with classical disuse syndromes.
The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin-or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. Methods:We measured transforming growth factor b signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n 5 11) or placebo (n 5 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase.Results: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p 5 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg 16.5% compared with placebo, p 5 0.024; left leg 17.6%, p 5 0.009) and lean body mass (15.7% compared with placebo, p 5 0.014). Subsequently, bimagrumabtreated patients had improved 6-minute walking distance, which peaked at 16 weeks (114.6%, p 5 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions.Conclusions: Transforming growth factor b superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. Classification of evidence:This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks. Neurology ® 2014;83:2239-2246 GLOSSARY ActRII 5 activin receptors IIA and IIB; DXA 5 dual-energy x-ray absorptiometry; LBM 5 lean body mass; pSMAD2/3 5 phosphorylated SMAD2/3; QMT 5 quantitative muscle testing; sIBM 5 sporadic inclusion body myositis; 6MWD 5 6-minute walking distance; TGFb 5 transforming growth factor b; TMV 5 thigh muscle volume.Sporadic inclusion body myositis (sIBM) is a slowly progressive degenerative and inflammatory skeletal muscle disease beginning in middle or later life.1 Its clinical features include a specific pattern of muscle involvement (preferential weakness of finger flexors and knee extensors) accompanied by progressive muscle atrophy, distinctive microscopic pathology including endomysial inflammation and rimmed vacuoles, and a recently identified serum autoantibody (against cytosolic 59-nucleotidase 1A) biomarker.2-4 Despite a prominent adaptive immune response characterized by antigen-stimulated B-and T-cell maturation and prominent infiltration into muscle of immune system cells, sIBM is highly refractory to immunosuppressive therapies studied to date. 2Members of the transforming growth factor b (TGFb) superfamily of ligands signal through a heterodimeric receptor system.5 They first bind a type II receptor, such as the TGFb...
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