ABSTRACT Background Pathological intramuscular lipid deposition (myosteatosis) and exercise intolerance are hallmarks of metabolic disorders, including diabetes and metabolic dysfunction‐associated steatotic liver disease (MASLD), yet their underlying mechanisms remain unclear. Our previous work has confirmed that hypertriglyceridemia‐driven kallistatin (KAL) elevation is present in the peripheral blood of patients with MASLD and diabetes and is a causative factor in hepatic steatosis and MASH pathogenesis. Here, we aim to evaluate this elevated KAL on myosteatosis and exercise function. Methods We first established rat models of myosteatosis via a high‐fat diet or high‐fructose water intake and measured serum KAL levels by immunoblotting. KAL transgenic (KAL‐TG) mice were generated and subjected to longitudinal analyses, including Oil Red O staining for lipid deposition, exercise tolerance tests, indirect calorimetry for energy expenditure, mitochondrial DNA copy number quantification, ATP measurement, immunoblotting and quantitative PCR. For mechanistic analyses, mouse C2C12 myotubes were treated with recombinant KAL or KAL adenovirus, with or without co‐treatment with AICAR, AdipoRon or AdipoR1 siRNA. Additionally, we evaluated the potential ameliorative effects of KAL knockout and target agonists on myosteatosis. Results Serum KAL levels were significantly elevated in rat models of myosteatosis. Conversely, genetic ablation of KAL ameliorated diet‐induced muscle lipid deposition. KAL‐TG mice developed myosteatosis (muscle TG μmol/g: WT: 54.26 ± 14.56 95% CI: 38.99–69.54; KAL‐TG: 85.13 ± 11.53 95% CI: 73.03–97.24, p < 0.01) and exhibited exercise intolerance ( p < 0.05 for all) from 6 months of age. Mechanistically, KAL bound to sarcolemmal adiponectin receptor 1 (AdipoR1), suppressing AMPK activity. This led to reduced phosphorylation of acetyl‐CoA carboxylase (ACC) ( p < 0.05), enhancing lipogenesis and downregulated the PGC‐1α/NRF1 axis ( p < 0.05), impairing mitochondrial biogenesis and reducing ATP production ( p < 0.05). Pharmacological activation of AdipoR1 (AdipoRon) and fenofibrate attenuated myosteatosis and restored exercise capacity in KAL‐TG mice ( p < 0.05). Conclusions Abnormal elevation of KAL drives metabolic myopathy and exercise intolerance by antagonizing the AdipoR1‐AMPK axis. Our findings offer dual strategies: repurposing AdipoR1 agonists (e.g., AdipoRon) or reducing circulating KAL (e.g., via genetic ablation or triglyceride‐lowering agents such as fenofibrate), both applicable to diabetes/MASLD‐related metabolic myopathy.
Hong et al. (Wed,) studied this question.