therapeutic target for skeletal muscle wasting

[Guest guest]

J Support Oncol. 2005 May-Jun;3(3):209-17.

The ubiquitin-proteasome pathway as a therapeutic target for muscle

wasting.

Tisdale MJ.

Cancer Biochemistry at the Pharmaceutical Sciences Research Institute, Aston

University, Birmingham, United Kingdom.

Atrophy of skeletal muscle is common to a number of conditions,

including cancer, sepsis, AIDS, renal failure, diabetes, severe

trauma, and burns. In all cases, protein synthesis in skeletal muscle

is depressed, whereas protein degradation is increased through an

increase in activity and expression of the ubiquitin-proteasome

proteolytic pathway. This pathway is not responsive to simple

nutritional intervention. Certain agents, including glucocorticoids,

cytokines, proteolysis-inducing factor (PIF), and oxidative stress,

are thought to be responsible for the induction of the ubiquitin-

proteasome pathway in skeletal muscle in catabolic conditions.

Insulin suppresses activation of this pathway, and loss of insulin

action in diabetes leads to muscle wasting. Cytokines, PIF, and

reactive oxygen species (ROS) are thought to induce proteasome

expression through activation of the transcription factor nuclear

factor kappa B (NF-kappaB). Targets for therapeutic intervention

include antagonists of the inducers of proteasome expression,

intracellular signaling pathways leading to activation of NF-kappaB,

and the enzymes inducing ubiquitin conjugation to the substrate

protein (myosin), as well as the proteasome itself. Anticytokine and

anti-PIF antibodies are effective in attenuating muscle protein

degradation in certain experimental animal models,and glucocorticoid

receptor antagonists are effective in the treatment of sepsis. Agents

that inhibit NF-kappaB activation, such as resveratrol, thalidomide,

ibuprofen, eicosapentaenoic acid, and beta-hydroxy-beta-

methylbutyrate, are effective in the preservation of skeletal muscle

mass in cachexia.These results suggest that the ubiquitin-proteasome

pathway is an appropriate therapeutic target to prevent muscle

wasting.