87 Peptides Mapped as Muscle Wasting Biomarkers and Drug Targets

Skeletal muscle wasting — encompassing sarcopenia and cachexia — affects millions globally, predicts increased mortality and disability, and imposes enormous economic costs. Yet biomarker development and effective pharmacological treatments remain limited. This scoping review, following PRISMA-ScR guidelines, systematically maps the emerging landscape of peptides as both biomarkers and therapeutic agents for muscle wasting.

Researchers searched Embase, PubMed, and Web of Science through October 2024, screening 2,004 unique records and ultimately including 126 studies from 22 countries. Studies were excluded if they involved congenital or inherited muscle disorders, inflammatory myopathies, neurodegenerative diseases, pure in vitro designs, or undefined peptide mixtures. Data covered peptide characteristics, study populations, muscle outcome measures (mass, strength, physical performance, or sarcopenia diagnosis), and cellular signaling mechanisms.

The review identified 87 distinct peptides ranging from a 3-amino-acid collagen tripeptide to the 51-amino-acid insulin. The five most studied were ghrelin (14.3% of studies), brain natriuretic peptide/BNP (11.1%), C-peptide (11.1%), insulin (10.3%), and the mitochondria-targeting peptide Szeto-Schiller 31/SS-31 (6.3%). Crucially, 62.1% of identified peptides were found to act through four central muscle homeostasis pathways: PI3K/Akt/mTOR, ActR/SMAD, IKK/NF-κB, and AMPK/PGC1α — regulating both atrophic signals (via FOXO, NF-κB, SMAD2/3, glucocorticoid receptor, GSK-3β) and hypertrophic signals (via androgen receptors, PGC-1α, S6K). This pathway mapping provides a mechanistic framework for prioritizing peptide candidates in drug development.

The review uncovered pervasive methodological shortcomings. Female subjects were dramatically underrepresented: only 23.9% of participants in human interventional studies were female, and just 9.1% of mice and 12.4% of rats used were female. Pre-analytical standardization was also poor — only 56.6% of studies documented diurnal timing, food intake, and physical activity around peptide collection, none specified storage-to-analysis duration, and only 11.5% reported assay detection limits.

The authors conclude that while the peptide-muscle wasting field is growing rapidly (more than half of all included studies published since 2018), progress toward clinical translation is hampered by sex bias, heterogeneous study populations skewed toward elderly humans and young rodents, and inadequate reporting standards. They advocate for machine learning tools to help identify novel bioactive peptides from vast sequence databases and for adherence to established biomarker reporting guidelines to accelerate discovery.