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Abstract: FR-OR122

Skeletal Muscle Inflammation and Fibrosis Contribute to Weakness in Patients with CKD

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1302 Health Maintenance, Nutrition, and Metabolism: Clinical

Authors

  • Abramowitz, Matthew K., Albert Einstein College of Medicine, New York, New York, United States
  • Paredes, William, Albert Einstein College of Medicine, New York, New York, United States
  • Zhang, Kehao, Einstein Medical School, Bronx, New York, United States
  • Brightwell, Camille, University of Texas Medical Branch, Galveston, Texas, United States
  • Newsom, Julia N., University of Texas Medical Branch, Galveston, Texas, United States
  • Kwon, Hyokjoon, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States
  • Custodio, Matthew, Albert Einstein College of Medicine, New York, New York, United States
  • Buttar, Rupinder singh, Jacobi medical center, Belmont, New York, United States
  • Farooq, Hina, Louis A. Weiss Memorial Hospital, Chicago, Illinois, United States
  • Zaidi, Bushra, BronxCare Health System, Bronx, New York, United States
  • Pai, Rima N., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Pessin, Jeffrey E., Albert Einstein College of Medicine, New York, New York, United States
  • Hawkins, Meredith, Albert Einstein College of Medicine, New York, New York, United States
  • Fry, Christopher, University of Texas Medical Branch, Galveston, Texas, United States
Background

Muscle dysfunction is an important cause of morbidity among patients with chronic kidney disease (CKD). Although muscle fibrosis is present in a CKD rodent model, its existence in humans and its impact on physical function are currently unknown. In animal models of muscle injury, TNF-α secreted by macrophages prevents muscle fibrosis by limiting the expansion of fibro/adipogenic progenitor cells (FAPs).

Methods

We examined isometric leg extension strength and measures of skeletal muscle fibrosis and inflammation in vastus lateralis muscle from CKD patients (n=10, stage 4 and 5 CKD) and healthy, sedentary controls of similar age (n=10). Histochemistry and immunohistochemistry were used to assess muscle collagen and macrophage and FAP cell populations, and RT-qPCR was used to assess muscle-specific inflammatory marker expression.

Results

Muscle collagen content was significantly greater in CKD compared with control (18.8 ± 6.7% vs. 11.7 ± 2.0% collagen area, p=0.008), as was staining for collagen I, pro-collagen I, and a novel collagen-hybridizing peptide that binds remodeling collagen. Muscle collagen was inversely associated with leg extension strength in CKD (r= -0.74, p=0.01) but not control (r=0.40, p=0.28). FAP abundance was increased in CKD, was highly correlated with muscle collagen (r=0.84, p<0.001), and was inversely associated with TNF-α expression (r= -0.65, p=0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF-α and IL-6. Immunohistochemistry confirmed fewer CD68+ and CD11b+ macrophages in CKD muscle.

Conclusion

Skeletal muscle collagen content is increased in humans with CKD and is functionally significant. Muscle fibrosis correlated with increased FAP abundance resulting from insufficient macrophage-mediated TNF-α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

Funding

  • NIDDK Support