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Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease
Keith G Avin1,2, Neal X Chen2, Jason M Organ3
1Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, IN, United States of America.
Abstract:
Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD.
Insights
Chronic kidney disease (CKD) in rats shows abnormal muscle regeneration and increased muscle breakdown, linked to oxidative stress and myostatin. These factors contribute to skeletal muscle dysfunction in CKD patients.
Area of Science:
- Nephrology
- Skeletal Muscle Physiology
- Biochemistry
Background:
- Skeletal muscle atrophy and dysfunction in chronic kidney disease (CKD) negatively impact quality of life and increase mortality risk.
- The underlying mechanisms of skeletal muscle dysfunction in CKD remain poorly understood.
Purpose of the Study:
- To investigate the molecular signaling pathways involved in skeletal muscle dysfunction in a rat model of chronic kidney disease (CKD).
Main Methods:
- Utilized a naturally occurring CKD rat model (Cy/+ rat) exhibiting hormonal abnormalities consistent with clinical CKD.
- Analyzed skeletal muscle gene and protein expression, including markers of regeneration, proteolysis, oxidative stress, and myostatin.
- Assessed plasma levels of oxidative stress markers and examined mitochondrial morphology.
Main Results:
- CKD rats displayed augmented skeletal muscle regeneration (increased MyoD, myogenin; decreased Pax-7) alongside elevated proteolytic markers (Atrogin-1, MuRF-1).
- CKD muscle exhibited increased oxidative stress (elevated 8-hydroxy-2'-deoxyguanosine, increased SDH and Nox4 expression, altered mitochondrial morphology).
- Significantly higher serum and muscle myostatin levels were observed in CKD rats compared to controls.
Conclusions:
- CKD is associated with aberrant skeletal muscle regeneration and enhanced proteolytic signaling.
- Oxidative stress and elevated myostatin levels are prominent features in the skeletal muscle of CKD rats.
- These molecular alterations likely contribute to the compromised skeletal muscle function observed in chronic kidney disease.
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