Abstract: PO0531
Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in the Absence and Presence of CKD
Session Information
- Bone and Mineral Metabolism: Causes and Consequences
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Heitman, Kylie, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Czaya, Brian A., University of California Los Angeles, Los Angeles, California, United States
- Campos, Isaac D., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Yanucil, Christopher, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Kentrup, Dominik, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Westbrook, David Gibbs, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Bollenbecker, Seth, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Krick, Stefanie, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
- Faul, Christian, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States
Background
Chronic Kidney Disease (CKD) is a public health epidemic and associated with elevated serum levels of phosphate (hyperphosphatemia) as well as skeletal muscle atrophy, and the interconnection is poorly understood. Elevated phosphate (Pi) has direct effects on smooth muscle cells and induces vascular calcification. We wanted to test if Pi directly induces atrophy in skeletal muscle cells. Furthermore, we analyzed skeletal muscle on a functional, histological and molecular level in three models of hyperphosphatemia – two CKD models, i.e. mice with global deletion of collagen 4a3 (Col4a3-/-) and wildtype mice receiving an adenine-rich diet, as well as wildtype mice on a high Pi diet with normal kidney function. Finally, we determined the effect of a low Pi diet on skeletal muscle in Col4a3-/- mice.
Methods
C2C12 myotubes were treated with 1-5 mM Pi for 24 hours, followed by qPCR expression analysis of atrophy genes (atrogenes), including MT1, Trim63, and Fbox32. Furthermore, we studied Col4a3-/- mice receiving normal chow or a 0.2% Pi diet at 10 weeks of age. We also analyzed C57Bl/6 mice receiving an adenine-rich (0.2%) diet for 14 weeks or a 3% Pi diet for 3 months. We analyzed grip strength, hindlimb area by MRI, muscle wet weight, cross-sectional area of individual muscle fibers immuno-labeled with anti-laminin by fluorescence microscopy, and expression levels of atrogenes by qPCR.
Results
Pi treatments increased the expression levels of atrogenes in C2C12 myotubes. In the three mouse models, grip strength and cross-sectional area of myofibers were significantly reduced, and the expression levels of atrogenes were significantly elevated when compared to respective controls. Additionally, the two CKD models showed significant reductions in muscle weight and hindlimb area. Administration of a 0.2% Pi diet protected Col4a3-/- mice from developing skeletal muscle atrophy.
Conclusion
Elevated Pi induces myotube atrophy in vitro. Mouse models with hyperphosphatemia develop skeletal muscle atrophy in the presence and absence of CKD, and a low Pi diet protects the skeletal muscle in CKD mice. Pharmacological approaches targeting Pi uptake or excretion, or inhibition of Pi’s direct actions on tissues might alleviate various CKD-associated pathologies.
Funding
- NIDDK Support