Muscle atrophy contributes to morbidity and mortality in aging and
chronic disease, emphasizing the need to gain understanding of the mechanisms involved in
muscle atrophy and (re)growth. We hypothesized that the magnitude of muscle regrowth during recovery from
atrophy determines whether myonuclear accretion and myogenic differentiation are required and that
insulin-like growth factor (
IGF)-I/Akt/
glycogen synthase kinase (GSK)-3beta signaling differs between regrowth responses. To address this hypothesis we subjected mice to hindlimb suspension (HS) to induce
atrophy of soleus (-40%) and plantaris (-27%) muscle. Reloading-induced muscle regrowth was complete after 14 days and involved an increase in IGF-IEa
mRNA expression that coincided with Akt phosphorylation in both muscles. In contrast, phosphorylation and inactivation of
GSK-3beta were observed during soleus regrowth only. Furthermore, soleus but not plantaris regrowth involved muscle regeneration based on a transient increase in expression of
histone 3.2 and
myosin heavy chain-perinatal, which are markers of myoblast proliferation and differentiation, and a strong induction of muscle regulatory factor (MRF) expression. Experiments in cultured muscle cells showed that
IGF-I-induced MRF expression is facilitated by inactivation of
GSK-3beta and selectively occurs in the myoblast population. This study suggests that induction of
IGF-I expression and Akt phosphorylation during recovery from
muscle atrophy is independent of the magnitude of muscle regrowth. Moreover, our data demonstrate for the first time that the regenerative response characterized by myoblast proliferation, differentiation, and increased MRF expression in recovering muscle is associated with the magnitude of regrowth and may be regulated by inactivation of
GSK-3beta.