Homma Kyoka, Enoki Yuki, Taguchi Kazuaki, Matsumoto Kazuaki
Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan.
Kidney360. 2025 Sep 1;6(9):1438-1447. doi: 10.34067/KID.0000000852. Epub 2025 Jun 4.
The decline mechanism in endurance exercise capacity from the early stages of CKD remains unclear. This study identifies TGF- as a key driver of oxidative-type muscle fiber atrophy in CKD, highlighting it as a potential therapeutic target. By reversing the altered muscle fiber composition through TGF- inhibition, exercise endurance capacity could be preserved in CKD.
Understanding the vicious cycle driving renal impairment progression and skeletal muscle atrophy in CKD is crucial. Therefore, this study aimed to examine the role of TGF- in promoting skeletal muscle atrophy in CKD.
A combined model of two/three nephrectomy and unilateral ureteral ligation, as we previously reported, was used for CKD mice. Skeletal muscle weight and changes in skeletal muscle fiber twitch type were evaluated. Using C2C12 cells, a skeletal muscle myoblast cell line, molecules that induce a reduction in type 2a muscle fibers in CKD were identified. The identified molecule, TGF-, was administered to mice to investigate its effects on muscle fiber-type changes. Furthermore, the effects of administering a TGF- inhibitor to CKD mice were evaluated.
In CKD mice, myosin heavy chain (MyHC)-specific antibody immunostaining showed an increase in atrophied MyHC 2a (oxidative twitch) muscle fibers. CKD mouse serum preferentially induces MyHC 2a fiber atrophy in C2C12 cells. TGF-treated mice had reduced levels of oxidative metabolic skeletal muscle and oxidative type 2a fiber, similar to CKD mice. Furthermore, TGF- inhibitor treatment prevented the CKD-associated decrease in oxidative type 2a muscle fiber size and reduced exercise capacity.
These findings indicate that TGF- causes skeletal muscle deterioration in CKD by reducing oxidative metabolism and inducing type 2a fiber atrophy. In addition, our results emphasize that reversing the disrupted MyHC phenotype in CKD is a potential therapeutic target for CKD-induced muscle atrophy.
慢性肾脏病（CKD）早期耐力运动能力下降的机制尚不清楚。本研究确定转化生长因子（TGF）-为CKD中氧化型肌纤维萎缩的关键驱动因素，突出其作为潜在治疗靶点的地位。通过抑制TGF-来逆转改变的肌纤维组成，CKD患者的运动耐力可得到保留。
了解驱动CKD中肾功能损害进展和骨骼肌萎缩的恶性循环至关重要。因此，本研究旨在探讨TGF-在促进CKD骨骼肌萎缩中的作用。
如我们之前报道的，采用双侧/三侧肾切除和单侧输尿管结扎的联合模型用于CKD小鼠。评估骨骼肌重量和骨骼肌纤维抽搐类型的变化。使用骨骼肌成肌细胞系C2C12细胞，鉴定出CKD中导致2a型肌纤维减少的分子。将鉴定出的分子TGF-给予小鼠，以研究其对肌纤维类型变化的影响。此外，评估了给CKD小鼠施用TGF-抑制剂的效果。
在CKD小鼠中，肌球蛋白重链（MyHC）特异性抗体免疫染色显示萎缩的MyHC 2a（氧化抽搐）肌纤维增加。CKD小鼠血清优先诱导C2C12细胞中MyHC 2a纤维萎缩。与CKD小鼠相似，TGF-处理的小鼠氧化代谢骨骼肌和氧化型2a纤维水平降低。此外，TGF-抑制剂治疗可防止CKD相关的氧化型2a肌纤维大小减少和运动能力降低。
这些发现表明，TGF-通过降低氧化代谢和诱导2a型纤维萎缩导致CKD中的骨骼肌恶化。此外，我们的结果强调，逆转CKD中破坏的MyHC表型是CKD诱导的肌肉萎缩的潜在治疗靶点。
