Preservation of NMJ in functional regeneration of skeletal muscle

Deterioration of neuromuscular junction (NMJ) integrity and function is causal to muscle atrophy and frailty, ultimately hindering quality of life and increasing the risk of death. In particular, NMJ is vulnerable to ischemia reperfusion (IR) injury when blood flow is restricted followed by restoration. However, little is known about the underlying mechanism(s) and hence the lack of effective interventions. New evidence suggests that mitochondrial oxidative stress plays a causal role in IR injury, which can be precluded by enhancing mitochondrial protein S-nitrosation (SNO). The Yan Lab is interested in elucidating the role of IR and mitochondrial protein SNO in skeletal muscle in clinically relevant animal model of skeletal muscle IR injury. The lab has shown that injection of a mitochondria-targeted S-nitrosation enhancing agent, MitoSNO, into ischemic muscle prior to reperfusion reduced mitochondrial oxidative stress in the motor nerve and NMJ, attenuated denervation at NMJ, and resulted in accelerated functional recovery of the muscle. These findings demonstrate that enhancing mitochondrial protein SNO protects against IR-induced denervation at NMJ in skeletal muscle and accelerates functional regeneration. The research team is also interested in the mechanism by which endurance exercise training provides profound protection in skeletal muscle against IR and promote functional regneration. These studies will improve the team's understanding of IR-induced muscle injury and promote development of interventions to protect skeletal muscle from IR injury.

Publications

Wilson RJ, Drake JC, Cui D, Zhang M, Perry HM, Kashatus JA, Kusminski CM, Scherer PE, Kashatus DF, Okusa MD, Yan Z. Conditional MitoTimer reporter mice for assessment of mitochondrial structure, oxidative stress, and mitophagy. Mitochondrion. 2017 Dec 20. pii: S1567-7249(17)30196-4. PubMed PMID: 29274400.

Wilson RJ, Drake JC, Cui D, Lewellen BM, Fisher CC, Zhang M, Kashatus DF, Palmer LA, Murphy MP, Yan Z. Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle. Free Radic Biol Med. 2018 Feb 9;117:180-190.PubMed PMID: 29432799. 

Wilson RJ, Drake JC, Cui D, Ritger ML, Guan Y, Call JA, Zhang M, Leitner LM, Gödecke A, Yan Z. Voluntary running protects against neuromuscular dysfunction following hindlimb ischemia-reperfusion in mice. J Appl Physiol (1985). 2018 Nov 15. doi: 10.1152/japplphysiol.00358.2018. [Epub ahead of print] PubMed PMID: 30433863.