CKD-Induced Oxidative Twitch Muscle Atrophy Is Mediated by TGF- β.

KEY POINTS

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.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.