Jin-Ho Koh^1,2,6, Mark W. Pataky^1,6, Surendra Dasari³, Katherine A. Klaus¹, Ivan Vuckovic⁴, Gregory N. Ruegsegger¹, Arathi Prabha Kumar¹, Matthew M. Robinson⁵ & K. Sreekumaran Nair^1,*

¹Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, United States. ²Department of Physiology, College of Medicine, Yeungnam University, Daegu, Korea. ³Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States. ⁴Mayo Clinic Regional Comprehensive Metabolomics Core, Mayo Clinic, Rochester, MN, United States. ⁵School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR 97331, United States. ⁶These authors contributed equally: Jin-Ho Koh, Mark W. Pataky.

^*Corresponding author.

Resistance exercise training (RET) is an effective countermeasure to sarcopenia, related frailty and metabolic disorders. Here, we show that an RET-induced increase in PGC-1α4 (an isoform of the transcriptional co-activator PGC-1α) expression not only promotes muscle hypertrophy but also enhances glycolysis, providing a rapid supply of ATP for muscle contractions. In human skeletal muscle, PGC-1α4 binds to the nuclear receptor PPARβ following RET, resulting in downstream effects on the expressions of key glycolytic genes. In myotubes, we show that PGC-1α4 overexpression increases anaerobic glycolysis in a PPARβ-dependent manner and promotes muscle glucose uptake and fat oxidation. In contrast, we found that an acute resistance exercise bout activates glycolysis in an AMPK-dependent manner. These results provide a mechanistic link between RET and improved glucose metabolism, offering an important therapeutic target to counteract aging and inactivity-induced metabolic diseases benefitting those who cannot exercise due to many reasons.