Kidney Week

Abstract: PO0529

Uremic Milieu Exacerbates Muscle Regeneration After Muscular Injury in Mice

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

• Higashihara, Takaaki, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Takaaki Higashihara, MD, PhD

• Nishi, Hiroshi, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Hiroshi Nishi,

• Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan

Masaomi Nangaku,

Background

In our life, skeletal muscle injuries occur not only in strenuous exercises but also in daily activities with unexpected excessive muscle contraction. In general conditions, injured muscles are repaired to normal structure, and muscle functions are rescued. However, whether this repair process is affected in the uremic milieu has not been fully elucidated yet.

Methods

In C57BL6 male mice fed with normal diet or 0.2% adenine-conjugated diet, the muscle injury was induced by intramuscular injection with vehicle (PBS) or barium chloride (BaCl₂) in tibialis anterior (TA) muscles. Then, we evaluated the TA muscle wet weight, histology, muscle strength, and marker gene expressions of Pax7⁺ satellite cells and macrophages playing a pivotal role in muscle regeneration. We also treated differentiating mouse skeletal myoblasts with a representative uremic toxin, indoxyl sulfate (IS), and evaluated the cell morphology and marker gene expressions.

Results

In adenine-induced CKD mice, the BaCl₂-injected TA muscle showed reduction of muscle wet weight, muscle fiber size, instantaneous muscle strength, and Pax7 gene expression compared to control mice. Furthermore, the gene expression of DLL1 and Notch2 regulating the Pax7 expression, CCL5 accelerating the migration of macrophages, and cell surface markers of M1/2 macrophages (CD206, CD163, and CD86) also decreased in the injured muscle of CKD mice. Treatment of murine C2C12 myoblast with IS led to not only the myotube atrophy but also smaller number of nuclei per myotube. The gene expression of Pax7, DLL1, and CCL5 increased during the C2C12 myoblast differentiation, but IS treatment deteriorated these expressions as seen in vivo experiments.

Conclusion

Uremic milieu deteriorated muscle regeneration with the decline of gene expression associated with satellite cells and macrophages.