Anabolic and catabolic responses to different modes of exercise in patients with chronic kidney disease

Muscle wasting is common in chronic kidney disease (CKD), contributing to impaired function and poor health outcomes. Exercise is recommended, but the molecular responses of skeletal muscle to different exercise modalities remain unclear. This study examined anabolic, catabolic, and myogenic responses to aerobic exercise (AE) versus combined exercise (CE; aerobic plus resistance) in CKD. Muscle biopsies were collected from participants in a 12-week randomized controlled trial (the ExTra CKD trial) at baseline, 24 hours after initial exercise bout (untrained), and 24 hours after the final session (trained). Western blotting and RT-qPCR assessed markers of protein synthesis, degradation, and regeneration. Complementary in vitro experiments used mechanically stretched primary skeletal muscle cells from CKD patients and healthy controls to investigate the temporal dynamics of anabolic signalling. AE did not alter Akt phosphorylation at any time point (p > 0.05). In contrast, CE showed no acute effect before training (p > 0.05) but significantly increased Akt phosphorylation after training (+118% vs baseline, p = 0.02), indicating partial restoration of anabolic signalling. CE also attenuated the acute increase in the 14-kDa actin fragment observed in the untrained state (+253%, p = 0.04), and increased expression of myogenic marker MyoD following training (p = 0.01), whereas AE effects were minimal (p > 0.05). In vitro mechanical stretch induced marked increases in Akt (CKD: +5651%, p = 0.012; healthy control: +3437%, p = 0.028) and p70S6K phosphorylation immediately post-stretch (CKD: +1076%, p = 0.014; healthy control: +712%, p = 0.038). No significant differences in the temporal signalling response were observed between CKD and healthy control cells (P-Akt: p = 0.84; P-P70S6K: p = 0.052). CE, but not AE alone, elicits beneficial anabolic and myogenic adaptations in skeletal in CKD. Combining in vivo and in vitro approaches offers deeper mechanistic insight into exercise-induced molecular adaptations and highlights the importance of including resistance training to overcome anabolic resistance in this population. This study includes analysis of tissue samples from two clinical trials both registered with the ISRCTN- ExTRa CKD: ISRCTN (no. 36489137, registered 21/04/2014) and Explore CKD: ISRCTN (No. 18221837, registered 10/02/2016).