Translational signalling, atrogenic and myogenic gene expression during unloading and reloading of skeletal muscle in myostatin-deficient mice.
Skeletal muscles of myostatin null (Mstn(-/-)) mice are more susceptible to atrophy during hind limb suspension (HS) than are muscles of wild-type mice. Here we sought to elucidate the mechanism for this susceptibility and to determine if Mstn(-/-) mice can regain muscle mass after HS. Male Mstn(-/-) and wild-type mice were subjected to 0, 2 or 7 days of HS or 7 days of HS followed by 1, 3 or 7 days of reloading (n = 6 per group). Mstn(-/-) mice lost more mass from muscles expressing the fast type IIb myofibres during HS and muscle mass was recovered in both genotypes after reloading for 7 days. Concentrations of MAFbx and MuRF1 mRNA, crucial ligases regulating the ubiquitin-proteasome system, but not MUSA1, a BMP-regulated ubiquitin ligase, were increased more in muscles of Mstn(-/-) mice, compared with wild-type mice, during HS and concentrations decreased in both genotypes during reloading. Similarly, concentrations of LC3b, Gabarapl1 and Atg4b, key effectors of the autophagy-lysosomal system, were increased further in muscles of Mstn(-/-) mice, compared with wild-type mice, during HS and decreased in both genotypes during reloading. There was a greater abundance of 4E-BP1 and more bound to eIF4E in muscles of Mstn(-/-) compared with wild-type mice (P<0.001). The ratio of phosphorylated to total eIF2α increased during HS and decreased during reloading, while the opposite pattern was observed for rpS6. Concentrations of myogenic regulatory factors (MyoD, Myf5 and myogenin) mRNA were increased during HS in muscles of Mstn(-/-) mice compared with controls (P<0.001). We attribute the susceptibility of skeletal muscles of Mstn(-/-) mice to atrophy during HS to an up- and downregulation, respectively, of the mechanisms regulating atrophy of myofibres and translation of mRNA. These processes are reversed during reloading to aid a faster rate of recovery of muscle mass in Mstn(-/-) mice.
Department of Sport and Exercise Science, University of Auckland, Auckland, New Zealand.
Heather K
HK
Smith
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Kenneth G
KG
Matthews
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Jenny M
JM
Oldham
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Ferenc
F
Jeanplong
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Shelley J
SJ
Falconer
Liggins Institute, University of Auckland, Auckland, New Zealand.
James J
JJ
Bass
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Mônica
M
Senna-Salerno
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Jeremy W
JW
Bracegirdle
AgResearch Ltd., Ruakura Agricultural Centre, Hamilton, New Zealand.
Christopher D
CD
McMahon
D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D005786:Gene Expression Regulation; D019417:Hindlimb Suspension; D008297:Male; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000378:metabolism; D055435:Myostatin / Q000172:deficiency* / Q000378:metabolism; D009929:Organ Size; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; D018995:Myosin Heavy Chains