Overexpression of NDRG2 in skeletal muscle does not ameliorate the effects of stress in vivo.
NEW FINDINGS
What is the central question of this study? Do elevated levels of the stress-response protein NDRG2 protect against fasting and chronic disease in mouse skeletal muscle? What is the main finding and its importance? NDRG2 levels increased in the tibialis anterior muscle in response to fasting and the effects of motor neurone disease. No alleviation of the stress-related and proteasomal pathways, mitochondrial dysfunction or muscle mass loss was observed even with the addition of exogenous NDRG2 indicating that the increase in NDRG2 is a normal adaptive response.


ABSTRACT
Skeletal muscle mass loss and dysfunction can arise from stress, which leads to enhanced protein degradation and metabolic impairment. The expression of N-myc 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 SOD1G93A 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 SOD1G93A 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.
['Mir|Bilal A|BA|', 'Mason|Shaun A|SA|', 'May|Anthony K|AK|', 'Russell|Aaron P|AP|0000-0002-5209-6134', 'Foletta|Victoria C|VC|0000-0002-7928-8451']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D002908:Chronic Disease D004195:Disease Models, Animal D059865:Endoplasmic Reticulum Stress D005215:Fasting D005260:Female D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D008928:Mitochondria D018482:Muscle, Skeletal D018384:Oxidative Stress D015398:Signal Transduction D013312:Stress, Physiological D013482:Superoxide Dismutase
NDRG2 skeletal muscle fasting SOD1G93A mice stress response N-myc downstream-regulated gene 2