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.
Highlights
Chronic kidney disease (CKD) is a progressive disease that leads to increased inflammation, increased concentrations of detrimental uremic toxins, augmented hormonal status and an impaired musculoskeletal system [1]
There was higher gene expression for muscle proteolytic markers Atrogin-1 and muscle ring finger protein 1 (MuRF-1) in extensor digitorum longus (EDL) from chronic kidney disease (CKD) compared to normal littermates (NLs) rats (Fig 2)
Our results demonstrate that in this progressive CKD rat model, muscle atrophy occurs despite increased satellite cell activation and differentiation, which may be attributed to activation of proteolytic pathways
Summary
Chronic kidney disease (CKD) is a progressive disease that leads to increased inflammation, increased concentrations of detrimental uremic toxins, augmented hormonal status and an impaired musculoskeletal system [1] These musculoskeletal deficits contribute to a lower health-related quality of life, greater disability, and reduced physical activity associated with increased risk of mortality [2,3,4]. Muscle dysfunction in CKD may be accelerated by either increased catabolism, decreased protein synthesis or impaired regeneration. It is not clear which are the overriding factors that sway the balance between muscle production and loss in CKD. It is not clear how these processes may be altered in a slow progressing, naturally occurring CKD model, which may better capture the progressive nature of human CKD
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