Weight gain does not preclude increased ubiquitin conjugation in skeletal muscle: an exploratory study in tumor-bearing mice.
OBJECTIVE
At least 13 studies have shown that the ubiquitin-proteasome system mediates muscle wasting in weight-losing cancer subjects. We hypothesized that cancer itself may activate the ubiquitin-proteasome system, regardless of weight loss.


METHODS
We utilized hybrid mice obtained by crossing Mouse Mammary Tumor Virus-Transforming Growth Factor-alpha (TGF-alpha) mice with the Lep(ob) strain. Five hybrid MMTV-TGF-alpha heterozygous Lep(+)Lep(ob) female mice with mammary tumors were used; 4 nontransgenic heterozygous Lep(+)Lep(ob) female mice served as controls. Ubiquitin conjugates were quantitated from hamstring and paraspinal muscles by Western blotting. Myocyte apoptosis was determined by a modified TUNEL assay.


RESULTS
All mice gained weight, even after tumor development. Higher concentrations of muscle ubiquitin conjugates were seen in the 5 tumor-bearing, TGF-alpha transgenic mice as compared with the 4 non-tumor-bearing mice: median (range) in arbitrary densitometric units: 0.67 (0.22-4.59) versus 0.18 (0.08-0.44) in hamstring muscle and 0.56 (0.23-20.15) versus 0.18 (0.08-0.25) in paraspinal muscle (p = 0.04 and p = 0.04, respectively; Mann-Whitney U test). Apoptosis was not seen in any muscle sample studied.


CONCLUSIONS
Ubiquitin conjugates are increased in the skeletal muscle of tumor-bearing mice in the absence of weight loss. Such activation is not seen in the skeletal muscle on non-tumor-bearing mice. Further studies might focus of whether this observation is relevant to cancer-associated wasting of lean tissue.
Jatoi
A
A
Department of Oncology, Mayo Clinic, Rochester, Minn 55455, USA.
Cleary
M P
MP
Tee
C M
CM
Nguyen
P L
PL
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002100:Cachexia / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D015430:Weight Gain / Q000502:physiology*
D009097:Multienzyme Complexes; D009124:Muscle Proteins; D016211:Transforming Growth Factor alpha; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex