Kidney dysfunction under cardiometabolic stress promotes calorie-intake-independent wasting and frailty-like muscle phenotypes

Although age-related sarcopenia and frailty are linked to impaired metabolic flexibility and disrupted energy homeostasis, whether this framework explains chronic kidney disease (CKD)-related wasting remains unclear. We show that superimposed nephron loss redirects cardiometabolic stress from obesity and glucose intolerance toward calorie-intake-independent wasting with sarcopenic and physical frailty features. This switch was accompanied by impaired skeletal muscle glucose-utilization programs, a blunted glycemic response to gluconeogenic substrates, and altered hepatic-renal gluconeogenic programs. Integrated omics revealed suppressed glucose programs, impaired fatty acid utilization-related compensation, and amino acid catabolic signatures in skeletal muscle. Similar features occurred with aging plus nephron loss and in older human CKD kidneys with reduced renal PCK1 expression. Cornstarch-based nutritional modulation improved exercise capacity, muscle mass, and serum albumin, highlighting slow-release carbohydrate modulation as a potential therapeutic entry point. These findings support a model in which kidney dysfunction promotes wasting by limiting systemic metabolic reserve and skeletal muscle metabolic flexibility.