Assessment of hindlimb myopathy and mitochondrial bioenergetics in a unique mouse model of access‐related hand dysfunction

Abstract

IntroductionAccess‐related hand dysfunction (ARHD) such as steal syndrome, neuromotor discoordination, and weakness is prevalent following arteriovenous fistula (AVF) placement in patients with end‐stage renal disease. Despite the progressive increase in symptomatic hemodialysis patients, currently no preclinical animal model exists to examine underlying mechanisms or develop novel therapeutics. Herein, we characterize the hindlimb pathology in a novel mouse model of iliac AVF.MethodsMale 8‐week‐old C57BL/6J mice were randomly assigned to casein‐based chow (CON: n=6) or adenine diet (CKD: n=16) for 3 weeks and glomerular filtration rate (GFR) using FIT‐C inulin clearance was measured. On the day of operation, animals were allocated to receive either left common iliac AVF (CKD_AVF: n=10) or Sham (CON_Sham: n=6, CKD_Sham: n=6) surgery and remained on their original diet throughout the study. Hemodynamic changes, hindlimb grip strength, and gait pattern were assessed prior to and post‐operatively. After two weeks of surgery, the animals were euthanized to assess gastrocnemius mitochondrial respiratory capacity and morphological alterations in tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles.ResultsAnimals exposed to adenine diet had impaired kidney function (GFR in CON:441.3±54.2 µL/min vs. CKD: 165.1±118.3 µL/min, p<0.01) prior to surgery. AVF placement increased inferior vena cava diameter (1.4‐fold at POD3 and 1.6‐fold at POD13, P<0.05) and peak velocity (3.3‐fold at POD3 and 3.8‐fold at POD13, P<0.05) when compared to the pre‐surgery values. In contrast to the animals with sham surgery, AVF mice had decreases in perfusion to the ventral paw (‐77.4±17.4% at POD0 and ‐30.7±15.8% at POD13, P<0.05), grip strength (‐58.6±35.1% at POD4 and ‐42.6±30.9% at POD12, P<0.05), and gait speed (‐5.7±5.2cm/sec at POD4, P<0.05 and ‐3.2±4.3 cm/sec at POD12, P=0.10). Gastrocnemius mitochondrial oxidative phosphorylation conductance in response to stress mimic conditions was decreased by both fistula formation and kidney insufficiency (P<0.05). Morphological analysis of limb muscles revealed that AVF mice exhibited ~60% of fibers with central nuclei and had ~35% smaller myofiber cross‐sectional area in TA and SOL muscles compared to CON_Sham (P<0.05) and ~50% lower capillary contacts in TA, EDL, and SOL muscles compared to both sham surgered groups (P<0.05).ConclusionIliac AVF creation resulted in central and peripheral hemodynamic alterations, impaired hindlimb neuromotor function, mitochondrial dysfunction, and morphological deformation. Taken together, we identify several key pathophysiological aspects of ARHD in a pre‐clinical model providing a platform to facilitate mechanistic and therapeutic studies aimed to reduce ARHD prevalence in CKD patients.