Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease

Abstract

Our evidence demonstrated that CKD upregulated the expression of myostatin, TNF-α, and p-IkBa and downregulated the phosphorylation of PI3K, Akt, and FoxO3a, which were also associated with protein degradation and muscle atrophy. The autophagosome formation and protein expression of autophagy-related genes were increased in muscle of CKD rats. The mRNA level and protein expression of MAFbx and MuRF-1 were also upregulated in CKD rats, as well as proteasome activity of 26S. Moreover, activation of myostatin elicited by TNF-α induces C2C12 myotube atrophy via upregulating the expression of autophagy-related genes, including MAFbx and MuRF1 and proteasome subunits. Inactivation of FoxO3a triggered by PI3K inhibitor LY294002 prevented the myostatin-induced increase of expression of MuRF1, MAFbx, and LC3-II protein in C2C12 myotubes. The findings were further consolidated by using siRNA interference and overexpression of myostatin. Additionally, expression of myostatin was activated by TNF-α via a NF-κB dependent pathway in C2C12 myotubes, while inhibition of NF-κB activity suppressed myostatin and improved myotube atrophy. Collectively, myostatin mediated CKD-induced muscle catabolism via coordinate activation of the autophagy and the ubiquitin-proteasome systems.

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

“…In addition, SNCA was increased by HS alone in muscles of vehicle treated animals, as SNCA gene expression was 3.6 fold greater in muscles from HS than cage control animals that were vehicle treated. The ubiquitously expressed TM9SF1 (MP70) may participate in autophagosome induction (He et al, 2009; Wang et al, 2015a). TM9SF1 gene expression was increased by 7 fold in EGCg treated cage control muscles, and while HS did not further upregulate this gene, it maintained gene expression at this high level because there was no difference in HS and vehicle treated EGCg muscles (Figure 1A, B).…”

“…For example, elevated autophagy signaling has been shown to occur in response to muscle disuse (Kang et al, 2016a; Kang et al, 2016b; White et al, 2015) and severe muscle wasting (Lokireddy et al, 2012; Wang et al, 2015). Autophagy has also been reported to increase in aging muscle (Pagano et al, 2015).…”

Reductions in skeletal muscle mitochondrial mass are not restored following exercise training in patients with chronic kidney disease

“…[1][2][3][4] This ultimately limits engagement in physical activity, reduces functional ability and is associated with high health and social care costs. For example, previous research has suggested a loss of muscle protein occurs primarily through an acceleration of protein degradation through the ubiquitin proteasome system 9 initiated by several factors including increased metabolic acidosis, 10,11 elevated myostatin signalling, 12 reduced insulin signalling, [13][14][15][16] and inflammation. [5][6][7][8] The mechanisms underlying muscle dysfunction and poor exercise capacity are complicated, multi-factorial and are likely to vary between individuals.…”

Myostatin serum concentrations are correlated with the severity of knee osteoarthritis

“…14 Mild to moderate severity of synovial inflammation could be found in approximately 33% of patients with OA after synovial biopsies are obtained. 16 TNF-α can activate myostatin through the NF-κB pathway in myotubes, 17 but inhibition of the NF-κB pathway can inactivate myostatin. 9 TNF-α stimulation enhanced the myostatin expression via the NF-κB pathway.…”

“…15 OA synovial fibroblasts incubated with inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-17 induce the upregulation of myostatin expression. 17 Moreover, silencing myostatin with myostatin antibody decreases TNF-α and IL-6 levels. By contrast, myostatin stimulates muscle cells releasing IL-6.…”