Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.
Our previous studies showed that adult (8 month) mice lacking CuZn-superoxide dismutase (CuZnSOD, Sod1KO mice) have neuromuscular changes resulting in dramatic accelerated muscle atrophy and weakness that mimics age-related sarcopenia. We have further shown that loss of CuZnSOD targeted to skeletal muscle alone results in only mild weakness and no muscle atrophy. In this study, we targeted deletion of CuZnSOD specifically to neurons (nSod1KO mice) and determined the effect on muscle mass and weakness. The nSod1KO mice show a significant loss of CuZnSOD activity and protein level in brain and spinal cord but not in muscle tissue. The masses of the gastrocnemius, tibialis anterior and extensor digitorum longus (EDL) muscles were not reduced in nSod1KO compared to wild type mice, even at 20 months of age, although the quadriceps and soleus muscles showed small but statistically significant reductions in mass in the nSod1KO mice. Maximum isometric specific force was reduced by 8-10% in the gastrocnemius and EDL muscle of nSod1KO mice, while soleus was not affected. Muscle mitochondrial ROS generation and oxidative stress measured by levels of reactive oxygen/nitrogen species (RONS) regulatory enzymes, protein nitration and F2-isoprostane levels were not increased in muscle from the nSod1KO mice. Although we did not find evidence of denervation in the nSod1KO mice, neuromuscular junction morphology was altered and the expression of genes associated with denervation acetylcholine receptor subunit alpha (AChRα), the transcription factor, Runx1 and GADD45α) was increased, supporting a role for neuronal loss of CuZnSOD initiating alterations at the neuromuscular junction. These results and our previous studies support the concept that CuZnSOD deficits in either the motor neuron or muscle alone are not sufficient to initiate a full sarcopenic phenotype and that deficits in both tissues are required to recapitulate the loss of muscle observed in Sod1KO mice.
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Kavithalakshmi
K
Sataranatarajan
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Rizwan
R
Qaisar
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Carol
C
Davis
MRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Giorgos K
GK
Sakellariou
MRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Aphrodite
A
Vasilaki
Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
Yiqiang
Y
Zhang
Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Yuhong
Y
Liu
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Shylesh
S
Bhaskaran
MRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Anne
A
McArdle
MRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
Malcolm
M
Jackson
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Susan V
SV
Brooks
Oklahoma VA Medical Center, Oklahoma City, OK 73104, USA; Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma City, OK, USA.
Arlan
A
Richardson
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma VA Medical Center, Oklahoma City, OK 73104, USA. Electronic address: holly-vanremmen@omrf.org.
Holly
H
Van Remmen
D000375:Aging; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D028441:F2-Isoprostanes / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D055948:Sarcopenia / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D028441:F2-Isoprostanes; D009687:Nuclear Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D011950:Receptors, Cholinergic; D013482:Superoxide Dismutase; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
CuZnSOD; Muscle atrophy; Neuromuscular junction; Oxidative stress; Sarcopenia