The Key to Muscle Regulation: GDF-8

Peptide-based weight loss drugs have swept the globe, but the side effects of these drugs are also significant. A substantial portion of the weight loss patients experience comes from indiscriminate muscle mass reduction, which can negatively affect muscle function and cause adverse reactions. GDF-8, a protein directly impacting muscle growth metabolism, has garnered increasing attention, becoming a crucial drug target for promoting muscle growth and treating muscle atrophy-related conditions.

Function and Signaling Pathway of GDF-8

GDF-8, a protein primarily expressed by skeletal muscle cells, stands for Growth/Differentiation Factor 8, also known as Myostatin or MSTN. It belongs to the Transforming Growth Factor-β (TGF-β) superfamily and mainly controls muscle volume by inhibiting muscle cell proliferation, thereby reducing muscle mass and regulating skeletal muscle growth. Under various pathological conditions, such as muscle atrophy, chronic kidney disease, cancer, liver disease, obesity, and anterior cruciate ligament (ACL) tears, GDF-8 levels may increase.

Figure 1: Maturation Process of GDF-8 [1]

Mature GDF-8 undergoes a series of cleavage processes: the GDF-8 precursor is synthesized within the cell and first has its signal peptide removed by signal peptidase, resulting in Pro-GDF-8 (also known as precursor GDF-8). Subsequently, the proprotein convertase Furin recognizes and cleaves specific sequences within Pro-GDF-8, forming Latent GDF-8. This step is crucial for GDF-8 maturation. Finally, the metalloproteinases BMP-1 or Tolloid further process Latent GDF-8, which may involve cleavage of the prodomain, thereby activating GDF-8. Mature GDF-8 exists as a homodimer, a structural feature critical for its biological activity.

Activin type II receptors (ActRII) are the main downstream receptors for GDF-8. When GDF-8 binds to them, it recruits ActRI receptors, subsequently activating intracellular SMAD and AKT signaling pathways. This leads to changes in gene transcription and the degradation of related proteins, ultimately causing muscle loss.

Figure 2: GDF-8 Signaling Pathway [2]

Development of GDF-8 Targeted Drugs

As a critical regulator of muscle growth and disease progression, GDF-8 is currently a significant target for treating skeletal muscle diseases, neuromuscular diseases, obesity, and cancer. Scholar Rock's SRK-015 (Apitegromab) is a representative drug in this category. SRK-015 is a fully human monoclonal antibody that binds with high specificity to human Pro-GDF-8 or Latent GDF-8 without binding to mature GDF-8 and other closely related growth factors. It inhibits GDF-8 before release, offering high selectivity and minimal side effects. SRK-015 is currently in Phase 3 clinical trials (NCT05156320) for spinal muscular atrophy (SMA) and is the first potential muscle-directed therapy for SMA. Roche's RO7204239 (GYM329, RG6237) targets Latent myostatin and is being tested for SMA (NCT05115110) and facioscapulohumeral muscular dystrophy (NCT05548556).

Figure 3: Design Principle of SRK-015 [3]

Regeneron's REGN-1033 (Trevogrumab) targets the mature form of GDF-8. In collaboration with Eli Lilly, Phase 2 clinical trials are evaluating whether Trevogrumab combined with Semaglutide±Garetosmab (anti-Activin A) can maintain weight loss efficacy by increasing muscle mass. Similarly, Keros' KER-065 is designed for GDF-8, being a novel ligand trap drug [4] that can capture GDF-8 or Activin A, treating obesity by increasing muscle mass and reducing fat mass. It can be used as a standalone therapy or combined with GLP-1 receptor agonists.

KACTUS High-Quality GDF-8 Products

Many drugs target non-mature forms of GDF-8, which may help control the activation process of GDF-8, while targeting the mature form of GDF-8 may directly intervene in muscle growth regulation. Drug design needs to consider the mechanism of action, safety, efficacy, and potential side effects to determine the most appropriate target.

To support drug development in metabolic diseases, cancer, and other fields, KACTUS has deeply invested in high-quality GDF-8 and related proteins, including both mature and non-mature forms. The products cover various species and diverse tag designs, all rigorously quality tested and applicable to different research stages such as drug screening and validation.

Product Validation Examples

Figure 4: Determined by its ability to inhibit the proliferation of MPC-11 cells. The expected ED50 for this effect is <30 ng/ml (QC Test).

Figure 5: Immobilized Human/Mouse/Rat GDF-8, No Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Human Activin RIIB, mFc Tag with the EC50 of 20.8 ng/ml determined by ELISA.

Available Proteins:

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References

[1]Hoogaars WMH, Jaspers RT. Past, Present, and Future Perspective of Targeting Myostatin and Related Signaling Pathways to Counteract Muscle Atrophy. Adv Exp Med Biol. 2018;1088:153-206. doi: 10.1007/978-981-13-1435-3_8.

[2]Garber K. No longer going to waste. Nat Biotechnol. 2016 May 6;34(5):458-61. doi: 10.1038/nbt.3557.

[3]https://scholarrock.com

[4]https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386654