Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype
Kavithalakshmi Sataranatarajan,
Rizwan Qaisar,
Carol Davis,
Giorgos K. Sakellariou,
Aphrodite Vasilaki,
Yiqiang Zhang,
Yuhong Liu,
Shylesh Bhaskaran,
Anne McArdle,
Malcolm Jackson,
Susan V. Brooks,
Arlan Richardson,
Holly Van Remmen
Affiliations
Kavithalakshmi Sataranatarajan
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Rizwan Qaisar
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Carol Davis
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
Giorgos K. 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 Vasilaki
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
Yiqiang Zhang
Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA
Yuhong Liu
Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Shylesh Bhaskaran
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
Anne 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 Jackson
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
Susan V. Brooks
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
Arlan Richardson
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
Holly Van Remmen
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma VA Medical Center, Oklahoma City, OK 73104, USA; Correspondence to: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, USA.
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. Keywords: CuZnSOD, Oxidative stress, Neuromuscular junction, Muscle atrophy, Sarcopenia
