Impact of N-acetylcysteine supplementation on skeletal muscle myopathy in a mouse model of access-related hand dysfunction

Abstract

Introduction: Hemodialysis is a life-line therapy for end-stage kidney disease patients that requires long-term arteriovenous access. Arteriovenous fistula (AVF) is the most durable and commonly employed access strategy. However, access-related hand dysfunction (ARHD) including ischemia, weakness, and neuromotor discoordination is prevalent (~50%) following AVF placement. Unfortunately, there are no pre-emptive non-surgical therapeutic studies available. We hypothesized that N-acetylcysteine (NAC) supplementation would attenuate hindlimb disability in a mouse model of ARHD. Methods: Adult male and female C57BL/6J mice (N=9/group) were fed adenine diet to induce kidney disease. Thereafter, animals were randomly allocated to receive NAC (150 mg/kg in 0.2 ml of 0.9% saline) or placebo (0.2 ml of saline) via oral gavage beginning 3 days prior to the AVF surgery and until euthanasia. Limb perfusion to the ischemic hindlimb and hindlimb grip strength were assessed post-operatively (POD) in vivo. Muscle contractile and mitochondrial function, and histological assessments of muscle and the neuromuscular junction were also performed. Results: Laser Doppler perfusion to the ventral paw was decreased immediately after AVF creation on the left common iliac artery (~25% of the contralateral limb) and recovered (~40-60%) at POD13 without a treatment effect. NAC treatment improved muscle mass in the tibialis anterior (TA) (+13~21%, P<0.05) and soleus (+17~21%, P<0.05) muscles in both male and female mice compared with placebo-treated animals. NAC female, not male, mice had significant improvement in grip strength (~20% greater at POD4 and POD12, P<0.05) and maximal mitochondrial respiration (~30% higher at POD14, P<0.05) compared with control animals. Muscle contractile function and myofiber area and capillarization in TA and soleus muscles were similar between NAC and placebo groups (P>0.05). Interestingly, the area of the post-synaptic acetylcholine receptor clusters was significantly greater in the animals that received NAC treatment (+10~22%, P<0.05) in both male and female mice. Conclusion: Daily treatment with a thiol reducing antioxidant, NAC, has beneficial effects on the recovery of muscle mass and neuromuscular junction morphology in both male and female mice with additional improvement in grip strength and mitochondrial function in female mice suggesting a potential therapeutic strategy targeting antioxidant defense to ameliorate ARHD. 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 2023 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.