Colocalization and Functional Analyses Identify GBE1 as a Gene Linking Muscle Strength and Cardiometabolic Fitness

Authors

• Theresia M. Schnurr, Stanford University School of Medicine
• Miranda L. Johnson, Stanford University School of Medicine
• Christopher Jin, Stanford University School of Medicine
• Kimmie V. Sørensen, Novo Nordisk Foundation Center for Basic Metabolic Research
• Lindsey Kim, Stanford University School of Medicine
• James W. Jahng, Stanford University School of Medicine
• Amanda Ramste, Stanford University School of Medicine
• Ewa Bielczyk-Maczynska, Stanford University School of Medicine
• Michael J. Gloudemans, Stanford University School of Medicine
• Peter Saliba-Gustafsson, Stanford University School of Medicine
• Elena Vinton, Stanford University School of Medicine
• Patrick L. Jurney, San Jose State UniversityFollow
• Ivan Carcamo-Orive, Stanford University School of Medicine
• Euan A. Ashley, Stanford University School of Medicine
• Torben Hansen, Novo Nordisk Foundation Center for Basic Metabolic Research
• Joshua W. Knowles, Stanford University School of Medicine
• Brian T. Palmisano, Stanford University School of Medicine

Publication Date

3-2-2026

Document Type

Article

Publication Title

American Journal of Physiology Endocrinology and Metabolism

Volume

330

Issue

3

DOI

10.1152/ajpendo.00470.2025

First Page

E380

Last Page

E389

Abstract

Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium-adjusted colocalization analysis of genome-wide association study summary statistics for handgrip strength, combined with expression and splicing quantitative trait loci from skeletal muscle, and identified glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPR-interference knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified upregulation of the human superoxide dismutase 2 and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.NEW & NOTEWORTHY Colocalization of genome-wide association study (GWAS) loci with quantitative trait loci (QTL) in skeletal muscle tissue identified GBE1 as a candidate for handgrip strength. Cellular phenotypes with GBE1 knockdown in immortalized human skeletal muscle cells include decreased glycogen content, accumulation of polyglucosan bodies, changes in mitochondrial function and morphology, and increased expression of reactive oxygen species (ROS) scavengers. Transcriptomic changes suggest a role for GBE1 in muscle contraction and oxidative stress-mediated responses.

Keywords

functional genomics, glycogen branching enzyme 1, handgrip strength, mitochondrial function, oxidative stress responses

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Department

Biomedical Engineering

Recommended Citation

Theresia M. Schnurr, Miranda L. Johnson, Christopher Jin, Kimmie V. Sørensen, Lindsey Kim, James W. Jahng, Amanda Ramste, Ewa Bielczyk-Maczynska, Michael J. Gloudemans, Peter Saliba-Gustafsson, Elena Vinton, Patrick L. Jurney, Ivan Carcamo-Orive, Euan A. Ashley, Torben Hansen, Joshua W. Knowles, and Brian T. Palmisano. "Colocalization and Functional Analyses Identify GBE1 as a Gene Linking Muscle Strength and Cardiometabolic Fitness" American Journal of Physiology Endocrinology and Metabolism (2026): E380-E389. https://doi.org/10.1152/ajpendo.00470.2025