IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the Apc Min/+ mouse

Abstract

BackgroundMuscle protein turnover regulation during cancer cachexia is being rapidly defined, and skeletal muscle mitochondria function appears coupled to processes regulating muscle wasting. Skeletal muscle oxidative capacity and the expression of proteins regulating mitochondrial biogenesis and dynamics are disrupted in severely cachectic ApcMin/+ mice. It has not been determined if these changes occur at the onset of cachexia and are necessary for the progression of muscle wasting. Exercise and anti-cytokine therapies have proven effective in preventing cachexia development in tumor bearing mice, while their effect on mitochondrial content, biogenesis and dynamics is not well understood. The purposes of this study were to 1) determine IL-6 regulation on mitochondrial remodeling/dysfunction during the progression of cancer cachexia and 2) to determine if exercise training can attenuate mitochondrial dysfunction and the induction of proteolytic pathways during IL-6 induced cancer cachexia.MethodsApcMin/+ mice were examined during the progression of cachexia, after systemic interleukin (IL)-6r antibody treatment, or after IL-6 over-expression with or without exercise. Direct effects of IL-6 on mitochondrial remodeling were examined in cultured C2C12 myoblasts.ResultsMitochondrial content was not reduced during the initial development of cachexia, while muscle PGC-1α and fusion (Mfn1, Mfn2) protein expression was repressed. With progressive weight loss mitochondrial content decreased, PGC-1α and fusion proteins were further suppressed, and fission protein (FIS1) was induced. IL-6 receptor antibody administration after the onset of cachexia improved mitochondrial content, PGC-1α, Mfn1/Mfn2 and FIS1 protein expression. IL-6 over-expression in pre-cachectic mice accelerated body weight loss and muscle wasting, without reducing mitochondrial content, while PGC-1α and Mfn1/Mfn2 protein expression was suppressed and FIS1 protein expression induced. Exercise normalized these IL-6 induced effects. C2C12 myotubes administered IL-6 had increased FIS1 protein expression, increased oxidative stress, and reduced PGC-1α gene expression without altered mitochondrial protein expression.ConclusionsAltered expression of proteins regulating mitochondrial biogenesis and fusion are early events in the initiation of cachexia regulated by IL-6, which precede the loss of muscle mitochondrial content. Furthermore, IL-6 induced mitochondrial remodeling and proteolysis can be rescued with moderate exercise training even in the presence of high circulating IL-6 levels.

Mitochondrial network regulation and its potential interference with inflammatory signals in pancreatic beta cells

“…STAT3 activation is well-known to be involved in the regulation of autophagy and also affects mitophagy [47]. Direct IL-6-induced effects on mitochondrial remodelling have been demonstrated in C2C12 myotubes [48], a finding in accordance with our own preliminary results on FIS1 and MFN2 expression in mouse pancreatic islets (S. Baltrusch, unpublished results). IL-6 treatment has been shown to increase FIS1 gene expression, which induces mitochondrial fission.…”

“…IL-6 treatment has been shown to increase FIS1 gene expression, which induces mitochondrial fission. In addition, downregulation of peroxisome proliferator-activated receptor γ co-activator 1-α (PGC1α) diminishes the induction of MFN2, resulting in reduced mitochondrial fusion and metabolism [48][49][50][51]. Thus, it is legitimate to speculate a possible imbalance in mitochondrial dynamics, with higher fission and reduced fusion in response to IL-6.…”

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

“…Increased serum levels of proinflammatory cytokines, including IL-6 and TNF-␣, play pivotal roles in tumor-induced muscle wasting (3,4,42). These cytokines increase activity of the ubiquitin proteasome and autophagy systems, promoting muscle protein breakdown (10,19,24).…”

Novel investigational drugs mimicking exercise for the treatment of cachexia

“…Consistently, PGC-1α has been recently shown to regulate mitophagy in the skeletal muscle (39) , while the reduced mitochondrial content reported in ApcMin/+ cachectic mice is associated with down-regulation of PGC-1α and mitochondrial fusion proteins (32) . Finally, both resistance and endurance exercise appear to stimulate the proliferation of SCs, promoting myogenesis (see above) (40) (41) .…”

“…C2C12 myotubes cultured in the presence of LLC cell conditioned medium show alterations of the electronic flow in the electron transport chain (31) and finally, muscle wasting in the ApcMin/+ mice, an experimental model of IL-6 driven cancer cachexia, is associated with altered expression of proteins regulating mitochondrial biogenesis and fusion (32) .…”