DDAH1 Protects against Cardiotoxin-Induced Muscle Injury and Regeneration

Abstract

Nitric oxide (NO) is an important biological signaling molecule affecting muscle regeneration. The activity of NO synthase (NOS) is regulated by dimethylarginine dimethylaminohydrolase 1 (DDAH1) through degradation of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). To investigate the role of DDAH1 in muscle injury and regeneration, muscle-specific Ddah1-knockout mice (Ddah1MKO) and their littermates (Ddah1f/f) were used to examine the progress of cardiotoxin (CTX)-induced muscle injury and subsequent muscle regeneration. After CTX injection, Ddah1MKO mice developed more severe muscle injury than Ddah1f/f mice. Muscle regeneration was also delayed in Ddah1MKO mice on Day 5 after CTX injection. These phenomena were associated with higher serum ADMA and LDH levels as well as a great induction of inflammatory response, oxidative stress and cell apoptosis in the gastrocnemius (GA) muscle of Ddah1MKO mice. In the GA muscle of CTX-treated mice, Ddah1 deficiency decreased the protein expression of M-cadherin, myogenin, Bcl-2, peroxiredoxin 3 (PRDX3) and PRDX5, and increased the protein expression of MyoD, TNFα, Il-6, iNOS and Bax. In summary, our data suggest that DDAH1 exerts a protective role in muscle injury and regeneration.

DDAH1 recruits peroxiredoxin 1 and sulfiredoxin 1 to preserve its activity and regulate intracellular redox homeostasis

“…Ddah1 deletion also attenuated the induction of SRXN1 and PRDX4 expression in the livers of CCl 4 -treated mice. The regulatory effects of DDAH1 on antioxidant enzymes have also been observed in PM 2.5 -exposed lungs [ 11 ] and in patients with cardiotoxin-induced muscle injury [ 9 ], acute myocardial infarction-induced heart failure [ 43 ] and diabetic nephropathy [ 10 ]. Notably, the underlying mechanism by which DDAH1 regulates antioxidant enzymes is complex and enzyme/cell/tissue dependent.…”

“…Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is recognized as a critical enzyme for the degradation of asymmetric dimethylarginine (ADMA) [ 6 ], which inhibits nitric oxide synthase (NOS) by competing with L-Arg. Our studies have consistently shown that DDAH1 can repress oxidative stress in different disease models, including fatty liver [ 7 , 8 ], muscle injury and regeneration [ 9 ], diabetic nephropathy [ 10 ] and PM 2.5 -exposed lung [ 11 ]. As ADMA accumulation under pathological conditions can promote ROS production by uncoupling NOS [ 12 ] or upregulating the renin–angiotensin system [ 13 ], the antioxidant effect of DDAH1 may be partly attributed to ADMA degradation.…”