title: Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy.
abstract: Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven- to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.
authors: Department of Biology of Physical Activity, Neuromuscular Research Center, University of Jyväskylä, Jyväskylä, Finland. juha.hulmi@jyu.fi
authors: Juha J
authors: JJ
authors: Hulmi
authors: Mika
authors: M
authors: Silvennoinen
authors: Maarit
authors: M
authors: Lehti
authors: Riikka
authors: R
authors: Kivelä
authors: Heikki
authors: H
authors: Kainulainen
mesh_terms: D000818:Animals; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C469992:Ddit4 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; D014157:Transcription Factors; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D045643:DNA Repair Enzymes