Abstract
BackgroundThe onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma.Methodology/Principal FindingsC26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p)-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059.Conclusions/SignificanceThese results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.
Highlights
Cancer cachexia is a multifactorial, multifaceted syndrome, in particular characterized by marked loss of body weight, depletion of fat and muscle mass and protein hypercatabolism in many tissues
Conclusions/Significance: These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could be proposed as a therapeutic target
Mitogen-Activated Protein Kinases (MAPKs) expression and phosphorylation status, this latter widely considered a reliable indicator of MAPK activation [8], were evaluated in the gastrocnemius muscle of two experimental models of cancer cachexia
Summary
Cancer cachexia is a multifactorial, multifaceted syndrome, in particular characterized by marked loss of body weight, depletion of fat and muscle mass and protein hypercatabolism in many tissues. The ubiquitin and proteasome system (UPS), in particular, seems to play a major role [1], additional proteolytic pathways were proposed to act upstream and downstream of the UPS to accomplish complete breakdown of myofibrillar proteins [2]. Other mechanisms possibly accounting for muscle depletion in cancer cachexia are downregulation of protein synthesis rates[4], or an impaired myogenic regenerative response [5]. The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. The present study investigated this point on mice bearing the C26 colon adenocarcinoma
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