Chronic kidney disease (CKD) is associated with muscle wasting, which contributes to increased patients mortality and disability. Researchers believe that CKD predisposes muscle atrophy by upregulating cellular pathways that elicit protein degradation. In certain diseases, autophagy – the degradation and recycling process of unnecessary or deteriorated cellular components – is activated in skeletal muscles, suggesting that this pathway might also contribute to muscle wasting in CKD. Skeletal muscle growth and differentiation is inhibited by myostatin, a secreted growth differentiation factor proteinmwhose levels increase with age, in muscle atrophy and in certain chronic diseases. However, myostatin general effects on muscle protein synthesis and degradation, and in particular in CKD are still not fully known and understood.
In a recent study, researchers from China used muscle cell lines and CKD rats to assess whether the ubiquitin-proteosome system – the principal mechanism of cellular protein degradation – and the autophagy pathway contribute for muscle atrophy in CKD. Moreover, researchers further investigated the role of myostatin in these cellular degradation and recycling processes. The work, entitled “Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease” was published in the Oxidative Medicine and Cellular Longevity journal.
The authors show that autophagy, the ubiquitin-proteosome system and myostatin expression levels are elevated in CKD muscle cells, resulting in muscle protein degradation and atrophy. The team further showed that myostatin overexpression was a result from inflammatory processes triggered by CKD, namely an increase in cytokine TNF-alpha levels in skeletal muscles, which promotes myostatin expression by the NF-kB pathway. Myostatin activates both the ubiquitin-proteosome system and autophagy by modulating PI3K/Akt/FoxO3a signalling pathway. The authors also showed that the CKD-mediated inflammatory conditions by itself activate several autophagy genes in muscle cells, further contributing for protein degradation and muscle wasting.
These findings highlight the crucial contribution of myostatin for muscle atrophy in CKD and suggest that targeting this signaling protein might be an interesting approach to prevent and treat muscle wasting in CKD.