ArticleThe Journal of clinical investigation2021
ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- ActIIR inhibition improves motor outcome and preserves muscle fibers after experimental autoimmune neuritis.Acta neuropathologica communications · 2026Article
- Cardiovascular remodeling: key mechanisms and clinical implications linking sarcopenia and heart failure.Frontiers in medicine · 2026Review
- CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis.Science (New York, N.Y.) · 2025Article
- Molecular constraints of sarcopenia in the ageing muscle.Frontiers in aging · 2025Review
- FNDC1 is a myokine that promotes myogenesis and muscle regeneration.The EMBO journal · 2025Article
- The role and mechanisms of myokines in sarcopenia: new intervention strategies for the challenges of aging.Frontiers in medicine · 2025Review
- A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.International journal of molecular sciences · 2024Review
- Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.International journal of molecular sciences · 2024Review
- Duchenne muscular dystrophy: pathogenesis and promising therapies.Journal of neurology · 2023Review
- A versatile Halo- and SNAP-tagged BMP/TGFβ receptor library for quantification of cell surface ligand binding.Communications biology · 2023Article
- Status of ALS Treatment, Insights into Therapeutic Challenges and Dilemmas.Journal of personalized medicine · 2022Review
- Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD.Biomedicines · 2022Article
- Exon skipping induces uniform dystrophin rescue with dose-dependent restoration of serum miRNA biomarkers and muscle biophysical properties.Molecular therapy. Nucleic acids · 2022Article
- Article
- Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors.iScience · 2022Article
- Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily.Scientific reports · 2021Article
- Review
- Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice.iScience · 2021Article
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.
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