Heat therapy preconditioning improves the skeletal muscle contractile and mitochondrial function in a mouse model of access-related hand dysfunction

Abstract

Introduction: Hemodialysis via arteriovenous fistula (AVF) is a life-line treatment for patients with end-stage kidney disease. However, hemodialysis access-related hand dysfunction (ARHD) including ischemia, muscle weakness and alterations in mitochondrial function is prevalent following AVF placement. We tested the hypothesis that two-weeks of daily heat therapy prior to AVF surgery would improve hindlimb function in a mouse model of ARHD. Methods: Adult male C57BL/6J mice (N=9-11/group) were fed a 0.2% adenine diet to induce chronic kidney disease. Following two weeks of the initial adenine diet, animals were randomly allocated to heat therapy (HT) or control (CON) groups. Animals assigned to HT were exposed to environmental heat at 40°C in a climate chamber for 30 min/day, six days/week, for two weeks while the control mice were exposed to room temperature (~22°C). The AVF was created using the left common iliac artery and vein 24-48 hours after the last treatment session. Laser Doppler perfusion to the ventral paw was assessed post-operatively (POD) and AVF patency was verified using a high-frequency duplex ultrasound system three days prior to euthanasia. Following 14 days of recovery, in situ tibialis anterior (TA) muscle contractility and gastrocnemius muscle mitochondrial function were assessed. RNA sequencing analysis of the hindlimb skeletal muscle (N=4/group) was performed. Results: Compared to baseline, the level of blood urea nitrogen was similarly elevated ( P<0.05) in both groups following four weeks of adenine diet. In both groups, blood perfusion to the paw was decreased by ~50% immediately after AVF creation and progressively recovered to ~80% at POD13 without a treatment effect ( P=0.4467). No differences in body weight and muscle mass in the TA, extensor digitorum longus, and soleus muscles were observed (all P>0.05). Notably, however, the absolute ( P=0.0250) and specific force ( P=0.0101) frequency relationship of the TA muscle were significantly improved in the animals exposed to HT. In addition, compared with control animals, HT mice had significant improvement in oxidative phosphorylation (OXPHOS) in both pyruvate ( P=0.0145) and octanoylcarnitine ( P=0.0196) fueled conditions. RNA sequencing results revealed that genes involved in nervous system development and metabolism were significantly different between HT and CON groups. Conclusion: Daily application of heat therapy for two weeks prior to the AVF surgery has beneficial effects on both skeletal muscle contractile and mitochondrial function suggesting this pre-habilitation strategy may mitigate the risk of ARHD in patients undergoing AVF surgery. Funding Support: National Institutes of Health grant R01HL148597 and American Heart Association grant POST903198. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.