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The DNA damage response after kidney injury induces cell cycle arrest in renal tubular epithelial cells, resulting in the secretion of pro-fibrotic cytokines, thereby promoting interstitial fibrosis in a paracrine manner. Phosphorylation of ataxia-telangiectasia mutated (ATM) is the initial step in the DNA damage response and subsequent cell cycle arrest; however, the effects of ATM inhibition on the injured kidney have not been explored. Pharmacological ATM inhibition by KU55933 in cisplatin-treated mice did not ameliorate, but instead exacerbated cisplatin-induced DNA damage and tubular injury, thereby increasing mortality. Analysis of isolated tubular epithelia by FACS from bigenic SLC34a1-CreERt2; R26tdTomato proximal tubular-specific reporter mice revealed that KU55933 upregulated p53 and subsequent pro-apoptotic signaling in tubular epithelia of cisplatin-treated mice, leading to marked mitochondrial injury and apoptosis. In addition, KU55933 attenuated several DNA repair processes after cisplatin treatment, including single-strand DNA repair and Fanconi anemia pathways, suggesting that DNA repair after dual treatment of cisplatin and KU55933 was not sufficient to prevent the cisplatin-induced tubular injury. Our study suggested that ATM inhibition does not increase DNA repair after cisplatin-induced DNA damage and exacerbates tubular injury through the upregulation of p53-dependent pro-apoptotic signaling. Acute kidney injury must be carefully monitored when ATM inhibitors become available in clinical practice in the future.

This study aimed to identify muscle synergies of the lower limb during treadmill running on level and inclined ground. Eight subjects ran on a treadmill at three speeds (2.5, 3.3, and 4.1 m/s) and two grades (level and 10% grade). Surface electromyographic (EMG) signals were recorded from 10 muscles of the lower limb, including deeper muscles such as vastus intermedius, adductor magnus, and adductor longus. Muscle synergies were extracted applying a non-negative matrix factorization algorithm, and relative co-activations across muscles and the temporal recruitment pattern were identified by muscle synergy vector and synergy activation coefficient, respectively. The scalar product between pairs of synergy vectors and synergy activation coefficients during level and uphill running conditions were analyzed as a similarity index, with values above 0.8 recognized as similar. Approximately 4 muscle synergies controlled the majority of variability in 10 EMGs during running, and were common between level and uphill conditions. At each running speed, inter-condition similarity was observed in synergy vector (r > 0.83) and synergy activation coefficients (r > 0.84) at each type of synergy. These results suggest that types of synergy are consistent between level and uphill running.