Cachexia in the non-obese diabetic mouse is associated with CD4+ T-cell lymphopenia.
One of the long-term consequences of Type I diabetes is weight loss with muscle atrophy, the hallmark phenotype of cachexia. A number of disorders that result in cachexia are associated with immune deficiency. However, whether immune deficiency is a cause or an effect of cachexia is not known. This study examines the non-obese diabetic mouse, the mouse model for spontaneous Type I diabetes, as a potential model to study lymphopenia in cachexia, and to determine whether lymphopenia plays a role in the development of cachexia. The muscle atrophy seen in patients with Type I diabetes involves active protein degradation by activation of the ubiquitin-proteasome pathway, indicating cachexia. Evidence of cachexia in the non-obese diabetic mouse was determined by measuring skeletal muscle atrophy, activation of the ubiquitin-proteasome pathway, and apoptosis, a state also described in some models of cachexia. CD4+ T-cell subset lymphopenia was measured in wasting and non-wasting diabetic mice. Our data show that the mechanism of wasting in diabetic mice involves muscle atrophy, a significant increase in ubiquitin conjugation, and upregulation of the ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F box/atrogin-1 (MAFbx), indicating cachexia. Moreover, fragmentation of DNA isolated from atrophied muscle tissue indicates apoptosis. While CD4+ T-cell lymphopenia is evident in all diabetic mice, CD4+ T cells that express a very low density of CD44 were significantly lost in wasting, but not non-wasting, diabetic mice. These data suggest that CD4+ T-cell subsets are not equally susceptible to cachexia-associated lymphopenia in diabetic mice.
Zhao
Chunfang
C
Torrey Pines Institute for Molecular Studies, General Atomics Court, San Diego, CA 92121, USA.
Wang
Zhuanzhi
Z
Robertson
Michael W
MW
Davies
Joanna D
JD
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002100:Cachexia / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D004326:Drinking; D004435:Eating; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis; D016130:Immunophenotyping; D008231:Lymphopenia / Q000150:complications* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D009124:Muscle Proteins / Q000032:analysis / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015431:Weight Loss
C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D004247:DNA; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases