ActRIIA and ActRIIB are important receptors for TGF-β superfamily ligands such as Myostatin/GDF8 and Activin A. Through SMAD2/3 signaling, they restrict skeletal muscle growth and participate in adipose tissue metabolism. Blocking ActRIIA/ActRIIB can increase or preserve Lean Mass while promoting Fat Mass reduction, making this pathway an important intervention direction for improving body composition during weight loss.

Keywords: ActRIIA; ActRIIB; Myostatin; Activin A; Bimagrumab; skeletal muscle; body composition

1 ActRIIA/ActRIIB and the Ligand Network

1.1 Receptor Positioning of ActRIIA and ActRIIB

ActRIIA is encoded by ACVR2A and ActRIIB by ACVR2B. Both are type II serine/threonine kinase receptors of the TGF-β superfamily. After a ligand binds ActRIIA/ActRIIB, type I receptors such as ALK4 and ALK7 are further recruited. The type II receptor phosphorylates and activates the type I receptor, which then transmits extracellular signals to the SMAD system. ActRIIA and ActRIIB have partially overlapping ligand spectra, so direct receptor blockade can simultaneously reduce input from multiple ligands, and its scope of action is generally broader than blockade of Myostatin or Activin A alone.

1.2 Myostatin, Activin A, and Related Ligands

(1) Myostatin/GDF8

Myostatin, also known as Growth Differentiation Factor 8 (GDF8), is mainly produced by skeletal muscle and is an important negative regulator that limits skeletal muscle growth. After mature Myostatin binds ActRIIA/ActRIIB, it activates SMAD2/3 through type I receptors such as ALK4, maintaining muscle cells in a growth-inhibited state. When effective Myostatin signaling is reduced, muscle fiber cross-sectional area and overall muscle mass can increase.

(2) Activin A

Activin A is encoded by INHBA and can likewise form receptor complexes through ActRIIA/ActRIIB. Compared with Myostatin, Activin A has a broader tissue origin and range of action. In skeletal muscle, it can work together with Myostatin to limit muscle growth while also participating in regulation of adipose tissue, bone, and other tissues. Therefore, blocking Myostatin alone cannot fully cover the negative regulatory signals mediated by ActRII.

(3) Other ActRII Ligands

TGF-β superfamily members such as GDF11 and Activin B can also utilize ActRIIA or ActRIIB to varying degrees. Differences in ligand composition, receptor expression levels, and type I receptor pairing among tissues make ActRIIA/ActRIIB common receptor nodes where multiple growth and metabolic signals converge.

1.3 Receptor Combinations in Skeletal Muscle and Adipose Tissue

In skeletal muscle, Myostatin and Activin A mainly form signaling complexes through ActRIIA/ActRIIB together with ALK4 and related receptors, maintaining SMAD2/3-mediated inhibition of muscle growth. In adipocytes, Activin-related signaling can also act through combinations of ActRII and ALK7 to participate in lipid storage and mobilization. Tissue-specific receptor combinations allow ActRII blockade to affect both skeletal muscle and adipose tissue rather than producing only a muscle-gain effect.

2 ActRIIA/ActRIIB-SMAD2/3 Signaling Mechanism

2.1 Formation of Type II and Type I Receptor Complexes

Myostatin or Activin A first binds ActRIIA/ActRIIB and promotes assembly of type II receptors with type I receptors such as ALK4 and ALK5. ActRIIA/ActRIIB phosphorylates type I receptors through its intracellular kinase activity, allowing the latter to further activate downstream SMAD proteins. ActRII blockade therefore acts at a signaling entry point shared by multiple ligands rather than directly inhibiting a single downstream effector molecule.

2.2 SMAD2/3-Mediated Transcriptional Regulation

Activated type I receptors phosphorylate SMAD2 and SMAD3. p-SMAD2/3 then forms a complex with SMAD4 and enters the nucleus, where it regulates genes related to myogenesis, protein metabolism, and cell growth. In skeletal muscle, sustained Myostatin/Activin-ActRII-SMAD2/3 signaling functions as a physiological growth restraint. When this signaling is reduced, inhibition of muscle fiber hypertrophy and muscle-mass increase is correspondingly weakened.

2.3 Relationship With AKT-Related Anabolic Signaling

After ActRII-SMAD2/3 signaling is reduced, skeletal muscle protein synthesis and hypertrophy-related networks are placed in a more favorable state, with signaling pathways such as AKT participating in this process. AKT activation favors protein synthesis and muscle-cell growth, but the increase in muscle after ActRII blockade does not depend entirely on a single AKT pathway and also involves SMAD-mediated transcriptional regulation and other muscle-growth networks.

3 Regulation of Skeletal Muscle by ActRIIA/ActRIIB

3.1 Restriction of Skeletal Muscle Growth

Myostatin and Activin A continuously provide negative growth signals through ActRIIA/ActRIIB, keeping muscle fiber size, protein synthesis, and myogenesis within a certain physiological range. Myostatin is particularly closely related to skeletal muscle-mass regulation. Enhanced Myostatin signaling favors loss of muscle mass, whereas reducing Myostatin-ActRII signaling can relieve part of the restriction on muscle-fiber growth.

3.2 Release of Muscle Growth Inhibition

Blocking ActRIIA/ActRIIB can simultaneously reduce effective signaling from multiple negative regulatory ligands such as Myostatin and Activin A, decreasing SMAD2/3 activity and relieving inhibition of skeletal muscle growth. This action occurs at the level of skeletal muscle growth regulation rather than through increased appetite or nutrient intake. It can therefore manifest as increased Lean Mass and Muscle Volume or reduced loss of lean tissue during substantial weight loss.

3.3 Lean Mass and Muscle Function

Lean Mass is not equivalent to Skeletal Muscle Mass and also includes water, organs, and other non-fat tissues. Therefore, changes in Lean Mass cannot all be directly interpreted as changes in skeletal muscle. ActRII studies should combine Muscle Volume, Muscle Fiber Cross-Sectional Area, muscle weight, and Muscle Strength, while distinguishing between increases in muscle mass and improvements in muscle function as two different outcome levels.

4 ActRIIA/ActRIIB and Adipose Regulation

4.1 ActRII-Related Signaling in Adipocytes

Activin-family signaling can regulate adipocyte function through receptor combinations involving ActRII and ALK7 and participate in lipid storage, lipolysis, and adaptation to nutritional status. When ActRII-related signaling is reduced, part of the regulation that maintains lipid storage in adipocytes is altered, potentially shifting lipid mobilization and net fat storage in a direction favorable to Fat Mass reduction.

4.2 Reduction in Fat Mass

The reduction in Fat Mass produced by ActRIIA/ActRIIB blockade does not primarily depend on directly reducing Food Intake. Increased skeletal muscle mass can alter substrate demand and energy allocation, while changes in ActRII-related signaling in adipose tissue may also directly affect lipid storage and mobilization. Therefore, muscle gain and fat loss are two interrelated body-composition effects after ActRII blockade but cannot be completely explained by one another.

4.3 Difference Between Body Weight and Body Composition

If ActRIIA/ActRIIB research observes only Body Weight, the actual effect can easily be underestimated. When Fat Mass decreases while Lean Mass increases, the two changes can partially offset one another in total body weight. Therefore, a relatively small decrease in body weight does not mean that there is no substantial change in body composition. For this class of drugs, Fat Mass, Lean Mass, and Muscle Volume usually have greater interpretive value than Body Weight alone.

Table 1 Major Body-Composition Indicators in ActRIIA/ActRIIB Research

5 ActRII Blockade and Myostatin Single-Target Blockade

5.1 ActRIIA/ActRIIB Receptor Blockade

ActRIIA/ActRIIB lies at the receptor level shared by multiple TGF-β superfamily ligands. Direct receptor blockade can simultaneously weaken input from Myostatin, Activin A, and other related ligands. Its characteristic is relatively broad signaling coverage that can affect both skeletal muscle and adipose tissue, but this also means that its biological scope is generally broader than neutralization of a single ligand.

5.2 Selective Myostatin Blockade

Myostatin-neutralizing antibodies mainly prevent GDF8 from binding ActRIIA/ActRIIB while preserving signaling from other ActRII ligands such as Activin A. This strategy focuses more specifically on Myostatin-dependent restriction of skeletal muscle growth. However, if Activin A also contributes substantially to negative regulation of muscle growth, the range of effects obtained by blocking Myostatin alone may be smaller than that obtained with dual-ligand or receptor-level blockade.

5.3 Dual Blockade of GDF8 and Activin A

Simultaneous neutralization of GDF8 and Activin A can remove two important negative regulatory inputs without directly shutting down the entire ActRII receptor system. The signaling coverage of this strategy lies between single-ligand blockade and ActRIIA/ActRIIB receptor blockade and is suitable for comparing the contributions of different intervention levels to Lean Mass preservation, muscle hypertrophy, and Fat Mass reduction.

Table 2 Different ActRII-Related Blockade Strategies

6 Representative ActRII-Related Drugs

6.1 Bimagrumab

(1) Dual ActRIIA/ActRIIB Receptor Blockade

Bimagrumab is a blocking antibody targeting ActRIIA and ActRIIB and can reduce effective signaling by endogenous ligands such as Myostatin and Activin A through both type II receptors. Unlike GLP-1R agonists, its primary action is not to reduce Food Intake but to directly alter ActRII signaling in skeletal muscle and adipose tissue.

(2) Increasing Lean Mass and Reducing Fat Mass

After Bimagrumab reduces ActRII signaling in skeletal muscle, Myostatin/Activin-related growth restriction can be relieved, while changes in ActRII-related adipose tissue signaling can promote Fat Mass reduction. Its typical characteristic is the simultaneous occurrence of increased or preserved Lean Mass and decreased Fat Mass, so Body Weight cannot fully reflect its effects.

(3) Combination With GLP-1R Agonists

GLP-1R activation mainly produces weight loss from the Energy Intake side, whereas ActRIIA/ActRIIB blockade directly regulates skeletal muscle and adipose tissue. When these two pharmacological mechanisms are combined, the proportion of Fat Mass reduction can be further increased while Lean Mass loss is reduced against the background of overall weight loss, shifting evaluation from the magnitude of weight loss alone toward the tissue composition of the weight lost.

6.2 Trevogrumab

Trevogrumab is a GDF8/Myostatin-targeting antibody that acts upstream of ActRIIA/ActRIIB and mainly reduces Myostatin input while preserving signaling from other ActRII ligands such as Activin A. This strategy is suitable for distinguishing the independent contribution of Myostatin to restriction of skeletal muscle growth and changes in Lean Mass during weight loss.

6.3 Garetosmab and Dual-Ligand Strategies

Garetosmab targets Activin A. When combined with a Myostatin-blocking strategy, it can simultaneously reduce two important negative regulatory inputs, GDF8 and Activin A. Dual-ligand blockade helps compare the differences among Myostatin blockade alone, GDF8+Activin A dual blockade, and ActRII receptor blockade and determine how different ranges of signaling coverage affect muscle preservation and Fat Mass changes.

Table 3 Representative ActRII-Related Drugs and Intervention Strategies

7 Complementarity Between ActRIIA/ActRIIB and GLP-1-Mediated Weight Loss

7.1 Food-Intake Control and Body-Composition Regulation

GLP-1R agonists mainly reduce Energy Intake through gastrointestinal-central regulation of food intake, whereas ActRIIA/ActRIIB blockade mainly alters the tissue composition of weight loss through effects on skeletal muscle and adipose tissue. The two mechanisms separately address the questions of “how much is consumed” and “which tissues account for the weight lost.” Therefore, combination strategies have clear mechanistic complementarity rather than redundantly enhancing the same food-intake-suppressing pathway.

7.2 Preservation of Lean Mass During Weight Loss

A certain degree of Lean Mass reduction accompanying substantial weight loss is not equivalent to Sarcopenia, nor can muscle functional impairment be inferred solely from decreased lean mass. The main value of ActRII-related strategies is to increase the proportion of total weight loss attributable to Fat Mass while maintaining or increasing skeletal muscle mass during weight loss, shifting drug evaluation from “how much weight was lost” toward “how much fat was lost and how much functional tissue was preserved.”

8 Key Experiments in ActRIIA/ActRIIB Research

8.1 Ligand-Receptor-SMAD Signaling

ActRII research first needs to distinguish receptor-level blockade from ligand-level blockade. Myostatin and Activin A stimulation together with ActRIIA/ActRIIB-related tools can be used to determine the level of action. p-SMAD2/3 is a classical downstream functional indicator, while Total SMAD2/3 is used to support interpretation of signaling changes. AKT and other protein-synthesis-related signals can supplement muscle-growth mechanism studies but cannot replace the ActRII-SMAD2/3 core axis.

8.2 Skeletal Muscle Phenotypes

Skeletal muscle studies should combine Muscle Mass, Muscle Volume, Muscle Fiber Cross-Sectional Area, and Muscle Strength. Lean Mass is suitable for whole-body body-composition analysis, but all changes in Lean Mass should not be directly attributed to skeletal muscle. In animal studies, further combining muscle tissue weight, histology, and functional testing can improve the accuracy of result interpretation.

8.3 Adipose and Body-Composition Evaluation

Fat Mass is the core endpoint for evaluating adipose-regulatory effects of ActRII blockade and can be combined with Total Body Fat, weights of different fat depots, TG, FFA, and related indicators. When combined with a GLP-1R agonist, Body Weight, Fat Mass, and Lean Mass should be reported separately to avoid using total weight-loss percentage alone to obscure differences in body composition among treatment strategies.

9 ActRIIA/ActRIIB-Related Research Products

9.1 ActRII Ligands, Receptors, and Signaling Research

9.2 Skeletal Muscle Structure and Metabolic Evaluation

9.3 Combined Weight-Loss and Lipid Metabolism Evaluation

ActRIIA/ActRIIB blockade weakens negative regulatory signals such as Myostatin and Activin A, thereby relieving restrictions on skeletal muscle growth and promoting Fat Mass reduction. Its value lies not only in reducing body weight but also in increasing the proportion of weight loss attributable to Fat Mass while preserving Lean Mass, providing a complementary mechanism for optimizing body composition during weight loss induced by GLP-1-class drugs.

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