**3. Mechanisms of TNF-α induced muscle catabolism**

In a pre-clinical proof of concept study Lang et al. [13] reported that a TNF-α infusion to rats reduced the muscle protein synthesis rate (decreased by 39%) by way of reducing the mRNA to protein conversion (decreased by 39%) of both myofibrillar and sarcoplasmic proteins in the gastrocnemius muscle. The plasma TNF-α concentration was raised to 500 pg/ml in this study.

A question that remains is: is it the plasma concentration of the TNF-α that is important and/or the muscle derived TNF-α [14] that is important in the regulation of muscle protein synthesis. A similar example in skeletal muscle are the acute phase proteins which are derived from muscle such as fibrinogen.

On the muscle protein breakdown side of the muscle mass equation, Li et al. [15] reported that TNF-α utilizes the p38 MAPK pathway to cause expression of atrogin-1/MAFBX in skeletal muscle. This activation of atrogin-1/MAFBX activates the ubiquitin-proteasome pathway for muscle protein degradation. This was confirmed when inhibitors of p38 inhibited ubiquitin conjugation activity.
