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Updated: Jun 28, 2025
Myo-mechanical Analysis of Isolated Skeletal Muscle
Published on: February 22, 2011
Uremia Impedes Skeletal Myocyte Myomixer Expression and Fusogenic Activity: Implication for Uremic Sarcopenia
Takaaki Higashihara1, Motoki Odawara1, Hiroshi Nishi1
1Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Abstract:
In patients with chronic kidney disease (CKD), skeletal muscle mass and function are known to occasionally decline. However, the muscle regeneration and differentiation process in uremia has not been extensively studied. In mice with CKD induced by adenine-containing diet, the tibialis anterior muscle injured using a barium chloride injection method recovered poorly as compared to control mice. In the cultured murine skeletal myocytes, stimulation with indoxyl sulfate (IS), a representative uremic toxin, morphologically jeopardized the differentiation, which was counteracted by L-ascorbic acid (L-AsA) treatment. Transcriptome analysis of cultured myocytes identified a set of genes whose expression was down-regulated by IS stimulation but up-regulated by L-AsA treatment. Gene silencing of myomixer, one of the genes in the set, impaired myocyte fusion during differentiation. By contrast, lentiviral overexpression of myomixer compensated for a hypomorphic phenotype caused by IS treatment. The split-luciferase technique demonstrated that IS stimulation negatively affected early myofusion activity that was rescued by L-AsA treatment. Lastly, in mice with CKD compared with control mice, myomixer expression in the muscle tissue in addition to the muscle weight after the injury was reduced, both of which were restored with L-AsA treatment. Collectively, data showed that the uremic milieu impairs the expression of myomixer and impedes the myofusion process. Considering frequent musculoskeletal injuries in uremic patients, defective myocyte fusion followed by delayed muscle damage recovery could underlie their muscle loss and weakness.
Insights
Uremia impairs muscle regeneration by reducing myomixer expression, hindering myocyte fusion. L-ascorbic acid (L-AsA) treatment rescues this defect, improving muscle recovery in chronic kidney disease (CKD) models.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- Chronic kidney disease (CKD) is associated with skeletal muscle decline.
- The mechanisms of impaired muscle regeneration in uremia remain unclear.
Purpose of the Study:
- To investigate the impact of uremic toxins on skeletal muscle regeneration and differentiation.
- To identify molecular targets for improving muscle recovery in CKD.
Main Methods:
- CKD model in mice induced by adenine diet.
- Barium chloride injection for muscle injury.
- In vitro studies using cultured murine skeletal myocytes.
- Stimulation with indoxyl sulfate (IS) and L-ascorbic acid (L-AsA).
- Transcriptome analysis, gene silencing, and lentiviral overexpression of myomixer.
- Split-luciferase assay for myofusion activity.
Main Results:
- CKD mice showed poor muscle recovery after injury.
- Indoxyl sulfate (IS) impaired myocyte differentiation and fusion, which L-ascorbic acid (L-AsA) counteracted.
- IS down-regulated myomixer expression; silencing myomixer impaired fusion, while overexpression rescued IS effects.
- IS inhibited myofusion activity, rescued by L-AsA.
- CKD mice had reduced muscle weight and myomixer expression, restored by L-AsA treatment.
Conclusions:
- The uremic environment, specifically indoxyl sulfate (IS), impairs skeletal muscle regeneration by inhibiting myomixer expression and myocyte fusion.
- L-ascorbic acid (L-AsA) can ameliorate these defects, suggesting a therapeutic potential for muscle loss in CKD patients.
