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Aim Voluntary exercise improves clinical outcomes in healthy subjects, but increased muscle ammoniagenesis may limit beneficial responses during hyperammonaemia in chronic diseases. Responses to 4‐weeks voluntary wheel running (VWR) were compared with usual activity (UA) to determine if hyperammonaemia alters VWR responses and if VWR alters muscle responses to hyperammonaemia. Methods Eight‐ to 10‐week‐old male C57BL/6J mice were treated with 6 weeks of subcutaneous infusion of 2.5 mmol kg−1 day−1 ammonium acetate (AmAc) or vehicle (PBS) via an osmotic pump. Two weeks after the start of infusion, mice were assigned to the intervention (VWR or UA). Wheel runs were measured, and weekly average rotations, distance, and circadian patterns were analysed. Indirect calorimetry was performed pre‐ and post‐intervention. Mice were euthanized 4 weeks after the start of VWR/UA, and organs (including muscles) were harvested, weighed, and muscle histomorphometry performed for fibre diameter/type. Protein synthesis by ex vivo puromycin incorporation, autophagy markers, expression of signalling proteins (mTORC1 pathway, eukaryotic initiation factor‐2‐α phosphorylation), and ammonia disposal enzymes were quantified by immunoblots. Mitochondrial oxidative function was measured by high‐sensitivity respirofluorometry using substrate, uncoupler, inhibitor, and titration protocols. Fluorometric assays were done for ammonia measurements. Results Gastrocnemius muscle mass (p < 0.01), muscle fibre area (p < 0.01), and grip strength were lower in AmAc‐UA than in PBS‐UA mice and higher with VWR than UA in AmAc mice (p < 0.001). Expression of electron transport chain proteins and some components of mitochondrial oxidative function were less (p < 0.05 or less) in AmAc‐UA than PBS‐UA, and these perturbations were reversed in the AmAc‐VWR mice (p < 0.05 or less). Global muscle protein synthesis (p < 0.05) and components of the mTORC1 pathway expression (p < 0.05) were higher, while myostatin expression was lower with VWR than UA in AmAc mice (p < 0.05). Expression of autophagy markers P62 and LC3‐II was not different with VWR or UA in AmAc mice, while Beclin1 was higher in VWR compared with UA, regardless of treatment group (p < 0.001). Expression of muscle ammonia disposal pathway enzymes, including glutamate dehydrogenase and pyrroline‐5‐carboxylate synthase, was higher (p ≤ 0.05) in AmAc‐UA versus PBS‐UA and increased in only PBS‐VWR mice (p < 0.05). Conclusion VWR reverses hyperammonaemia‐induced sarcopenia, protein synthesis/autophagy signalling perturbations, and mitochondrial oxidative dysfunction. Muscle mass, grip strength, signalling, and mitochondrial responses to VWR were not affected by hyperammonaemia. Increased expression of enzymes involved in the ammonia disposal pathway in skeletal muscle may be an adaptive response to hyperammonaemia. These data provide the rationale for exercise programmes in chronic diseases, including cirrhosis, even with hyperammonaemia.

Background Skeletal muscle is a major target for ethanol‐induced perturbations, leading to sarcopenia in alcohol‐related liver disease (ALD). The complex interactions and pathways involved in adaptive and maladaptive responses to ethanol in skeletal muscle are not well understood. Unlike hypothesis‐driven experiments, an integrated multiomics‐experimental validation approach provides a comprehensive view of these interactions. Methods We performed multiomics analyses with experimental validation to identify novel regulatory mechanisms of sarcopenia in ALD. Studies were done in a comprehensive array of models including ethanol‐treated (ET) murine and human‐induced pluripotent stem cell–derived myotubes (hiPSCm), skeletal muscle from a mouse model of ALD (mALD) and human patients with alcohol‐related cirrhosis and controls. We generated 13 untargeted datasets, including chromatin accessibility (assay for transposase accessible chromatin), RNA sequencing, proteomics, phosphoproteomics, acetylomics and metabolomics, and conducted integrated multiomics analyses using UpSet plots and feature extraction. Key findings were validated using immunoblots, redox measurements (NAD+/NADH ratio), imaging and senescence‐associated molecular phenotype (SAMP) assays. Mechanistic studies included mitochondrial‐targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) to increase redox ratio and MitoTempo as a mitochondrial free radical scavenger. Results Multiomics analyses revealed enrichment in mitochondrial oxidative function, protein synthesis and senescence pathways consistent with the known effects of hypoxia‐inducible factor 1α (HIF1α) during normoxia. Across preclinical and clinical models, HIF1α targets (n = 32 genes) and signalling genes (n > 100 genes) (n = 3 ATACseq, n = 65 phosphoproteomics, n = 10 acetylomics, n = 6 C2C12 proteomics, n = 106 C2C12 RNAseq, n = 64 hiPSC RNAseq, n = 30 hiPSC proteomics, n = 3 mouse proteomics, n = 25 mouse RNAseq, n = 8 human RNAseq, n = 3 human proteomics) were increased. Stabilization of HIF1α (C2C12, 6hEtOH 0.24 ± 0.09; p = 0.043; mALD 0.32 ± 0.074; p = 0.005; data shown as mean difference ± standard error mean) was accompanied by enrichment in the early transient and late change clusters, −log(p‐value) = 1.5–3.8, of the HIF1α signalling pathway. Redox ratio was reduced in ET myotubes (C2C12: 15512 ± 872.1, p < 0.001) and mALD muscle, with decreased expression of electron transport chain components (CI–V, p < 0.05) and Sirt3 (C2C12: 0.067 ± 0.023, p = 0.025; mALD: 0.41 ± 0.12, p = 0.013). Acetylation of mitochondrial proteins was increased in both models (C2C12: 107364 ± 4558, p = 0.03; mALD: 40036 ± 18 987, p = 0.049). Ethanol‐induced SAMP was observed across models (P16: C2C12: 0.2845 ± 0.1145, p < 0.05; hiPSCm: 0.2591, p = 0.041). MitoLbNOX treatment reversed redox imbalance, HIF1α stabilization, global acetylation and myostatin expression (p < 0.05). Conclusions An integrated multiomics approach, combined with experimental validation, identifies HIF1α stabilization and accelerated post‐mitotic senescence as novel mechanisms of sarcopenia in ALD. These findings show the complex molecular interactions leading to mitochondrial dysfunction and progressive sarcopenia in ALD.

A 30-year-old woman with history of passage of stones since childhood presented with oliguria and pedal edema for 10 days. She had hypertension with a creatinine of 4.1 mg/dL. Evaluation showed presence of bilateral multiple renal calculi with features of chronicity of kidney disease. Metabolic work-up for nephrolithiasis turned out to be negative and eventually renal biopsy revealed features of chronic interstitial nephritis with greenish brown refractile crystals in the tubular lumen and interstitium. The possibility of dihydroxy adenine crystalline nephropathy was considered. Spectrophotometry of RBC lysates revealed decreased activity of Adenine phosphoribosyl-transferase enzyme. Gene amplification by PCR and sequential analysis identified a missense mutation in exon 3 region of APRT gene in the patient and her family members. This case report highlights the need to contemplate the diagnosis of DHA crystalline nephropathy in young patients with nephrolithiasis and the identification of a rare genetic mutation, which is being reported for the first time in India.