Muscle preservation during GLP-1 weight loss: the myostatin and activin axis

A reduction in bodyweight does not come exclusively from adipose tissue. Body composition also changes through loss of lean mass, a broad term that includes skeletal muscle but also water, organs and other non-fat tissues. Ryan's 2025 review reports that approximately 45% of weight lost with semaglutide and about 25% with tirzepatide was attributed to lean mass. These percentages are aggregate estimates from specific body-composition data, not a prediction for every individual and not evidence that all of the change represents functional skeletal muscle.

Loss of muscle and bone accelerates beyond age 60, so the same lean-mass change may have different implications in an older population than in younger adults. The research interest extends beyond the number on a scale: it asks whether weight loss preserves strength, mobility and metabolic function. Reviews emphasize that functional-outcome and long-term safety data remain insufficient, so an increase in measured lean mass does not automatically equal a clinical benefit.

Myostatin and activins belong to the TGF-β superfamily and signal through activin type II receptors, known as ActRII. In skeletal muscle, this signaling acts as a constraint on muscle growth. The pharmacological strategy is therefore to reduce that signal selectively, either with an antibody against the receptor or by trapping or inhibiting specific ligands. The biology is compelling, but intervening in an axis with multiple ligands and tissues demands careful attention to selectivity, safety and genuine functional effects.

Bimagrumab is a monoclonal antibody that inhibits ActRII receptor signaling. The randomized Phase 2 NCT03005288 trial is the central proof of concept: in adults with type 2 diabetes and overweight or obesity, Heymsfield and colleagues reported a −20.5% change in fat mass and a +3.6% change in lean mass at 48 weeks, versus −0.5% and −0.8%, respectively, with placebo. These were outcomes in a specific, relatively small Phase 2 population, not established clinical practice or guidance for use.

NCT06643728 studies bimagrumab and tirzepatide, alone and in combination, in adults with obesity or overweight. The registration describes a Phase 2 study of 252 participants and is listed as active, not recruiting. The question is whether strong weight reduction through the incretin pathway can be combined with ActRII inhibition to alter the distribution between fat and lean mass. The registration documents the design, not the outcome; no published final data yet support conclusions about the combination.

Regeneron's NCT06299098 studies trevogrumab alone or with garetosmab on a semaglutide background, with objectives that include weight loss, fat loss and lean-mass preservation. Trevogrumab targets myostatin, while garetosmab targets activin A, allowing researchers to examine whether combining ligand targets changes body composition. NCT06445075 evaluated apitegromab in obesity and is now listed as completed, without published outcomes. NCT07281495 studies taldefgrobep alfa in adults with overweight and obesity and is listed as active, not recruiting. All remain development programmes without confirmed outcomes for this use.

Bimagrumab, trevogrumab, apitegromab, taldefgrobep alfa and garetosmab are monoclonal antibodies or other biologics. They are not research peptides and are not catalogue items on AllPeptides.eu. They appear here exclusively for bibliographic reasons, because their mechanisms illuminate a current body-composition research field. Their inclusion does not imply availability, recommendation or interchangeability.

ACE-031 is a soluble ActRIIB decoy designed to trap ligands in the myostatin/activin axis. Its clinical development was discontinued, and its historical importance lies in mechanism rather than validated therapeutic use. Follistatin-344 connects to the biology of natural follistatin, a protein that antagonizes myostatin and activins. Both pages exist on AllPeptides.eu as educational Research Use Only references. Human evidence for their use as muscle-preserving agents is limited and older; they are not equivalents or substitutes for the antibodies now under investigation.

Follistatin illustrates why this axis is biologically powerful but difficult. As an endogenous protein it binds more than one member of the activin family, while modern pharmacological approaches seek different degrees of selectivity against receptors, myostatin or activin A. Moving from a natural regulatory system to an antibody is not merely a change in format: it changes affinity, duration, tissue distribution and adverse-effect profile. A shared relationship to the ActRII axis therefore does not make these agents interchangeable.

The discussion is moving from how much weight is lost to which tissues account for that change and whether function is preserved. Bimagrumab provided an early human proof of concept for simultaneous fat-mass reduction and lean-mass increase, while trevogrumab, garetosmab, apitegromab and taldefgrobep alfa map the next generation. ACE-031 and follistatin-344 help explain the research history of the mechanism, not predict clinical efficacy. Until larger, long-term studies with functional outcomes are published, the field remains promising but developmental. This review is exclusively educational, bibliographic and Research Use Only.