Activating the NRK Pathway Improves NAD+ Recycling in Muscle Disorders: Preclinical Findings

Synopsis

Hexose-6-Phosphate Dehydrogenase (H6PD) produces NADPH inside the endoplasmic/sarcoplasmic reticulum (ER/SR), helping activate glucocorticoid hormones. However, its broader role in maintaining NAD(P)(H) balance in the ER/SR is not fully understood. Without H6PD, mice develop worsening muscle disease, glucose problems, and stress in the ER that triggers protective responses. This study examined muscle from mice lacking H6PD alone or together with Nicotinamide Riboside Kinase 2 (NRK2), a key enzyme in NAD+ production. H6PD-deficient muscles showed increased activity in NAD+ production pathways, especially the NRK2 pathway, but had poor mitochondrial function and altered metabolism. Giving these mice nicotinamide riboside to boost NAD+ raised NAD+ levels but did not improve mitochondrial problems or ER stress. Also, removing NRK2 didn’t worsen muscle disease or mitochondrial function despite lowering NAD+. These results suggest that changes in ER/SR NADPH levels trigger complex muscle metabolism changes and that boosting NAD+ alone cannot fix the mitochondrial and ER stress caused by lack of H6PD. It remains unclear if NRK2 activation is a direct response to ER/SR redox changes or a reaction to energy deficits.

Journal

Skeletal Muscle