Translational Signalling, Atrogenic and Myogenic Gene Expression during Unloading and Reloading of Skeletal Muscle in Myostatin-Deficient Mice

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.

Time-Course of Muscle Mass Loss, Damage, and Proteolysis in Gastrocnemius following Unloading and Reloading: Implications in Chronic Diseases

“…Besides, the cross-sectional areas of both type I and type II fibers were also significantly larger after seven days of hindlimb reloading and thereafter in the R cohorts of mice. Similar findings were also reported for the gastrocnemius in myostatin deficient mice exposed to muscle unloading and reloading (weight-bearing model) of the hindlimb [51]. Collectively, these findings suggest that the time-course of molecular and cellular events follows a very consistent pattern during muscle reloading following disuse muscle atrophy.…”

Muscle wasting in patients with end‐stage renal disease or early‐stage lung cancer: common mechanisms at work

“…Hdm2 is a ubiquitous E3 ligase mostly known for its role in p53 ubiquitination during cancer development, but it is also up‐regulated in muscles from hindlimb suspended rats, a model of hypokinesia . Finally, Fbxo30/MUSA1 is a muscle‐specific E3 ligase that was described as essential for the development of muscle atrophy in several rodent models with the exception of mild renal failure in rats, but Fbxo30/MUSA1 targets remain to be discovered . The recruitment of E3 ligases in catabolic patients was further demonstrated at the proteome level.…”

Epigallocatechin-3-gallate increases autophagy signaling in resting and unloaded plantaris muscles but selectively suppresses autophagy protein abundance in reloaded muscles of aged rats

“…MURF1 is ROS sensitive autophagy related ubiquitin ligase that is greatly increased in atrophying muscles (Bedard et al, 2015; Gomes et al, 2012; Smith et al, 2014; Tanner et al, 2015). ROS, and in sarcopenic muscles from old rats (Alway et al, 2014a; Alway et al, 2015; Hao et al, 2011; Ziaaldini et al, 2015).…”