Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

Abstract

Hulmi JJ, Silvennoinen M, Lehti M, Kivelä R, Kainulainen H. Altered redd1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy. Am J Physiol Endocrinol Metab 302: E307-E315, 2012. First published November 8, 2011 doi:10.1152/ajpendo.00398.2011.-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.

Myostatin Induces DNA Damage in Skeletal Muscle of Streptozotocin-induced Type 1 Diabetic Mice

“…Here, our results have established Mstn-mediated down-regulation of REDD1 and p63 levels via ROS production. However, recently, Hulmi et al reported an increase in p63 and REDD1 levels in STZ-treated mice at week 1 of STZ treatment plausibly due to higher dose of STZ (180 mg/kg) and/or the type of muscles used in the study (8). Our results indicated that the basal levels of REDD1 and p63 were higher in Mstn Ϫ/Ϫ mice probably in part due to higher levels of AMP-activated protein kinase (AMPK) in these mice (40) because AMPK was shown to stimulate REDD1 in vitro (41).…”

“…Mice injected with an equal volume of sodium citrate buffer were maintained as control groups. Nonfasting body weight and random blood glucose levels were determined on the day of injection and subsequently on Day 1,2,4,5,7,8,9,11,12,13,14,15,16, and 18. Mice were fasted for 9 -10 h and body weight and fasting blood glucose was measured on Day 3, 6, 10, and 17.…”

“…Our laboratory has shown recently that Mstn can induce ROS and in turn Anti-oxidant enzymes in skeletal muscle through TNF-␣ and NADPH oxidase (Nox) in a feed-forward manner (6). Previously it was reported that Mstn expression and level was up-regulated in skeletal muscle of rodents with type 1 diabetes induced by Streptozotocin (STZ) (7,8,9). Furthermore, Mstn expression was attenuated by insulin administration in STZ-induced type 1 diabetic mice (7).…”

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

“…The gastrocnemius muscle was pulverized in liquid nitrogen and homogenized in ice-cold buffer with proper inhibitors and further treated as reported previously (25). One part of the homogenate was taken for the protein puromycin incorporation examination.…”

“…However, some other genes in the Hippo pathway, such as Taz, Mst1, and Lats2, were unchanged (unpublished data). We also reanalyzed our previous microarray data from skeletal muscle in streptozotocin-induced diabetes (25). It was found that the mRNA level of YAP is not affected significantly in diabetic muscle atrophy or in exercised muscle (microarray data are available under accession no.…”