Overexpression of NDRG2 in skeletal muscle does not ameliorate the effects of stress in vivo

Abstract

Skeletal muscle mass loss and dysfunction can arise from stress, which leads to enhanced protein degradation and metabolic impairment. The expression of Nmyc downstream-regulated gene 2 (NDRG2) is induced in response to different stressors and is protective against the effects of stress in some tissues and cell types. Here, we investigated the endogenous NDRG2 response to the stress of fasting and chronic disease in mice and whether exogenous NDRG2 overexpression through adeno-associated viral (AAV) treatment ameliorated the response of skeletal muscle to these conditions. Endogenous levels of NDRG2 increased in the tibialis anterior muscle in response to 24 h fasting and with the development of the motor neurone disease, amyotrophic lateral sclerosis, in SOD1 G93A transgenic mice. Despite AAV-induced overexpression and increased expression with fasting, NDRG2 was unable to protect against the activation of proteasomal and stress pathways in response to fasting. Furthermore, NDRG2 was unable to reduce muscle mass loss, mitochondrial dysfunction and elevated oxidative and endoplasmic reticulum stress levels in SOD1 G93A mice. Conversely, elevated NDRG2 levels did not exacerbate these stress responses. Overall, increasing NDRG2 levels might not be a useful therapeutic strategy to alleviate stress-related disease pathologies in skeletal muscle.