Inhibition of skeletal muscle atrophy during torpor in ground squirrels occurs through downregulation of MyoG and inactivation of Foxo4.
Foxo4 and MyoG proteins regulate the transcription of numerous genes, including the E3 ubiquitin ligases MAFbx and MuRF1, which are activated in skeletal muscle under atrophy-inducing conditions. In the thirteen-lined ground squirrel, there is little muscle wasting that occurs during hibernation, a process characterized by bouts of torpor and arousal, despite virtual inactivity. Consequently, we were interested in studying the regulatory role of Foxo4 and MyoG on ubiquitin ligases throughout torpor-arousal cycles. Findings indicate that MAFbx and MuRF1 decreased during early torpor (ET) by 42% and 40%, respectively, relative to euthermic control (EC), although MuRF1 expression subsequently increased at late torpor (LT). The expression pattern of MyoG most closely resembled that of MAFbx, with levels decreasing during LT. In addition, the phosphorylation of Foxo4 at Thr-451 showed an initial increase during EN, followed by a decline throughout the remainder of the torpor-arousal cycle, suggesting Foxo4 inhibition. This trend was mirrored by inhibition of the Ras-Ral pathway, as the Ras and Ral proteins were decreased by 77% and 41% respectively, at ET. Foxo4 phosphorylation at S197 was depressed during entrance and torpor, suggesting Foxo4 nuclear localization, and possibly regulating the increase in MuRF1 levels at LT. These findings indicate that signaling pathways involved in regulating muscle atrophy, such as MyoG and Foxo4 through the Ras-Ral pathway, contribute to important muscle-specific changes during hibernation. Therefore, this data provides novel insight into the molecular mechanisms regulating muscle remodeling in a hibernator model.
Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
Yichi
Y
Zhang
Department of Surgery and Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA.
Shannon N
SN
Tessier
Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada. Electronic address: kenneth.storey@carleton.ca.
Kenneth B
KB
Storey
D000818:Animals; D001284:Atrophy / Q000503:physiopathology*; D015536:Down-Regulation; D006605:Hibernation / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D018008:Myogenin / Q000096:biosynthesis*; D010766:Phosphorylation; D012589:Sciuridae / Q000502:physiology*; D015398:Signal Transduction; D064348:Torpor / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism
D018008:Myogenin; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D020725:ral GTP-Binding Proteins
Foxo4; Ictidomys tridecemlineatus; Immunoblotting; MAFbx; Muscle remodeling; Ubiquitin ligase