Abstract
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.
Highlights
Skeletal muscles atrophy when their normal workload, including habitual weight-bearing activity, is reduced
The current data confirm our previous report that Mstn(2/2) mice are more susceptible to muscle atrophy than wild-type mice during Hind limb suspension (HS) [12]
We show that despite a greater loss of muscle mass during unloading, the wet mass and cross-sectional area of myofibres has largely recovered in Mstn(2/2) mice after seven days of reloading
Summary
Skeletal muscles atrophy when their normal workload, including habitual weight-bearing activity, is reduced. The reinstatement of weight-bearing, or reloading, leads to subsequent regrowth and recovery of the muscle [1,2,3,4,5]. In this regard, myostatin is a key gene regulating muscle mass. At odds with that postulate, we have shown that the absence of myostatin rendered mice more susceptible to loss of muscle mass during HS, which suggests that myostatin is not required for muscle atrophy [12]. The role of myostatin in the regrowth of disused skeletal muscle has yet to be considered
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