Aerobic Exercise Protects against Cardiotoxin-Induced Skeletal Muscle Injury in a DDAH1-Dependent Manner

TL;DR

Aerobic exercise helps protect skeletal muscle from injury caused by cardiotoxin, and this protection depends on the DDAH1 enzyme.

Contribution

This study demonstrates that DDAH1 is essential for the protective effects of aerobic exercise on skeletal muscle injury.

Findings

Aerobic exercise in wild-type mice reduced inflammation, oxidative stress, and apoptosis after cardiotoxin injury.

Ddah1MKO mice did not benefit from aerobic exercise in terms of muscle injury or regeneration.

Aerobic exercise increased DDAH1 expression and decreased ADMA levels in wild-type mice.

Abstract

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a critical enzyme that regulates nitric oxide (NO) signaling through the degradation of asymmetric dimethylarginine (ADMA). Previous studies have revealed a link between the beneficial effects of aerobic exercise and the upregulation of DDAH1 in bones and hearts. We previously reported that skeletal muscle DDAH1 plays a protective role in cardiotoxin (CTX)-induced skeletal muscle injury and regeneration. To determine the effects of aerobic exercise on CTX-induced skeletal muscle injury and the role of DDAH1 in this process, wild-type (WT) mice and skeletal muscle-specific Ddah1-knockout (Ddah1MKO) mice were subjected to swimming training for 8 weeks and then injected with CTX. In WT mice, swimming training for 8 weeks significantly promoted skeletal muscle regeneration and attenuated inflammation, oxidative stress, and apoptosis in the gastrocnemius (GA) muscle after CTX injection. These phenomena were associated with increases in the protein expression of PAX7, myogenin, MEF2A, eNOS, SOD2, and peroxiredoxin 5 and decreases in iNOS expression in GA muscles. Swimming training also decreased serum ADMA levels and increased serum nitrate/nitrite (NOx) levels and skeletal muscle DDAH1 expression. Interestingly, swimming training in Ddah1MKO mice had no obvious effect on CTX-induced skeletal muscle injury or regeneration and did not repress the CTX-induced inflammatory response, superoxide generation, or apoptosis. In summary, our data suggest that DDAH1 is important for the protective effect of aerobic exercise on skeletal muscle injury and regeneration.

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