Sarcopenia’s genetic architecture differs between sexes, genome-wide study finds

The growing global burden of sarcopenia—the progressive loss of skeletal muscle mass and strength that accompanies aging—has long outpaced the scientific tools available to predict, prevent, and treat it. Now, a large-scale genetic study has delivered one of the most comprehensive pictures yet of the biology underlying this condition, and in doing so has revealed something striking: the genetics of muscle health look remarkably different in men and women. In a genome-wide association study published in the journal Biology of Sex Differences, a team of researchers led by Yumeng Mu, Binzhi Liao, and colleagues at the Second Affiliated Hospital of Chongqing Medical University mined genetic and clinical data from the UK Biobank to map the genomic architecture of the sarcopenia index, a blood-based biomarker of muscle mass. Their analysis uncovered 774 independent genetic loci associated with the index, 367 of which had never before been linked to sarcopenia-related traits, and it demonstrated that the genetic drivers of muscle decline are substantially stratified by sex.

The sarcopenia index itself is an elegantly simple measure. It is calculated as the ratio of serum creatinine to cystatin C—two compounds routinely measured in standard blood panels. Creatinine is produced primarily by muscle tissue as a byproduct of energy metabolism, so higher circulating levels generally indicate greater muscle mass. Cystatin C, by contrast, is produced by virtually all nucleated cells and is cleared by the kidneys at a relatively steady rate, making it a useful normalizing factor for kidney function. The ratio between the two therefore offers a proxy for muscle mass that is adjusted for renal function, and it can be computed inexpensively from blood tests that millions of people already undergo. Despite its practical appeal, the genomic basis of this index had remained largely unexplored until now. The new study set out to fill that gap, asking not only which genetic variants influence the index but whether those influences differ between women and men.

To answer these questions, the researchers performed both combined-sex and sex-stratified genome-wide association studies, or GWAS, scanning hundreds of thousands of common genetic variants across the genomes of UK Biobank participants. In the combined-sex analysis, they identified 747 unique independent loci associated with the sarcopenia index. When they analyzed men and women separately, the picture became even richer: 283 loci reached genome-wide significance in the male-stratified analysis and 311 in the female-stratified analysis, bringing the total across all analyses to 774 unique independent loci. Notably, 247 of these loci achieved significance in only one sex, and 59 showed stronger associations in the corresponding sex-stratified analysis than in the combined one. This pattern underscores a growing recognition in human genetics that pooling the sexes can obscure biologically meaningful signals—signals that may be crucial for understanding diseases that manifest differently in men and women.

Among the most intriguing findings was the behavior of a specific genomic region on chromosome 15, at position 15q21.1, near the gene GATM, tagged by the variant rs1145093. GATM encodes glycine amidinotransferase, the rate-limiting enzyme in creatine biosynthesis—a pathway directly tied to muscle energy metabolism and, by extension, to the creatinine component of the sarcopenia index itself. Using a fine-mapping approach called CARMA, which integrates summary statistics across studies to pinpoint likely causal variants, the team identified sex-differentiated causal variants within this region. In other words, the same stretch of DNA appears to exert different effects on the sarcopenia index depending on whether the carrier is male or female, a finding that highlights how sex-specific hormonal and physiological contexts can modulate genetic risk.

Beyond individual loci, the researchers employed a battery of computational methods to move from statistical associations to biological mechanisms. They performed credible gene prioritization to identify the genes most likely to underlie the associations in each sex, arriving at 17 male-biased and 11 female-biased credible genes. They then examined whether the associated variants were enriched in motifs and binding sites for transcription factors—proteins that switch genes on and off—and the results painted a vivid hormonal portrait. In men, the genetic signals were significantly enriched near binding sites for the androgen receptor and GATA4, consistent with the central role that testosterone and related hormones play in maintaining muscle mass. In women, the signals pointed instead to ESR1, the gene encoding the estrogen receptor, and MYOD1, a master transcription factor that governs muscle differentiation and regeneration. This convergence suggests that androgen-driven pathways dominate the genetic regulation of muscle health in men, while estrogen-driven and muscle-regeneration pathways carry more weight in women.

Yet the analysis also revealed deep commonalities between the sexes. Gene-set enrichment analyses indicated that variants associated with the sarcopenia index in both men and women cluster in biological pathways involving inflammation, cellular stress responses, and aging-related processes. This shared architecture is consistent with the established understanding of sarcopenia as a condition driven in part by chronic low-grade inflammation—sometimes called “inflammaging”—and by the accumulation of cellular damage over time. Techniques such as linkage disequilibrium score regression, which estimates the overall genetic correlation between traits based on genome-wide data, allowed the team to place the sarcopenia index within a broader landscape of human disease, with consequences that could reshape how clinicians think about muscle health.

Those correlations proved to be consequential. The sarcopenia index showed an inverse genetic correlation with heart failure, with a genetic correlation coefficient of −0.19 and a p-value of 2.30 × 10⁻⁹, meaning that genetic factors predisposing to lower sarcopenia index values also predispose to heart failure. A similar inverse relationship was observed with metabolic syndrome, at a genetic correlation of −0.12 and a p-value of 8.49 × 10⁻⁸. In contrast, the index showed a positive genetic correlation with chronic kidney disease, an expected relationship given that both creatinine and cystatin C are kidney-cleared biomarkers. Taken together, these findings suggest that the sarcopenia index is not merely a measure of muscle but a genetically anchored node connecting muscle biology to cardiovascular, metabolic, and renal health. Low muscle mass, by this account, is not an isolated geriatric complaint but a measurable risk factor embedded in a web of chronic disease.

The sex-stratified analysis also uncovered differences in how the sarcopenia index intersects with metabolic traits. Cross-phenotype colocalization—a statistical method that tests whether the same causal variant drives associations for two different traits in the same genomic region—revealed that male SI exhibited two additional loci showing colocalization with four metabolic traits compared with female SI. Specifically, the variants rs1229984 at chromosome 4q23 and rs9817452 at chromosome 3q25.31 showed male-stratified colocalization with these metabolic traits. The rs1229984 variant is particularly well known: it lies in the ADH1B gene region and is famous for its role in alcohol metabolism, but its connection to metabolic traits in men through the lens of the sarcopenia index adds a new dimension to its biology. These results imply that the metabolic consequences of the genetic determinants of muscle mass may unfold differently in men, potentially through pathways involving alcohol metabolism and other sex-influenced processes.

The implications of this work extend well beyond basic genetics. Sarcopenia affects a substantial proportion of adults over sixty and is associated with falls, fractures, disability, hospitalization, and mortality, yet it is frequently underdiagnosed. Because the sarcopenia index relies on blood tests that are already part of routine clinical care, the genetic findings could eventually inform precision risk assessment—identifying, for example, individuals whose genetic profiles place them at elevated risk of accelerated muscle loss, particularly in ways that differ by sex. The identification of sex-specific transcription factor pathways also offers concrete molecular targets for intervention. Drugs or lifestyle strategies designed to modulate androgen signaling, estrogen signaling, or muscle regeneration pathways might need to be tailored differently for men and women, a principle that remains underappreciated in many clinical trials and prevention programs.

The study also demonstrates the power of revisiting biomarkers through the lens of sex-stratified genomics. Had the researchers analyzed only the combined sample, 247 loci that are significant in one sex would have been diluted or lost entirely. By explicitly modeling sex as a biological variable, the team exposed a genetic architecture that is layered: a substantial shared foundation, built on inflammation, stress response, and aging, overlaid with sex-specific regulatory circuits governed by hormones and sex-biased gene expression. The authors emphasize that these findings clarify the genetic architecture of the sarcopenia index and reveal sex-dependent mechanisms underlying sarcopenia, supporting precision risk assessment and targeted interventions. As the world’s population ages, understanding why men and women lose muscle differently—and how their genomes encode those differences—may prove to be one of the most practical lessons to emerge from this remarkable map of muscle biology.