Wnt10b Deficiency Promotes Coexpression of Myogenic and Adipogenic Programs in Myoblasts

Abstract

Adult myoblasts retain plasticity in developmental potential and can be induced to undergo myogenic, adipogenic, or osteoblastogenic differentiation in vitro. In this report, we show that the balance between myogenic and adipogenic potential in myoblasts is controlled by Wnt signaling. Furthermore, this balance is altered during aging such that aspects of both differentiation programs are coexpressed in myoblasts due to decreased Wnt10b abundance. Mimicking Wnt signaling in aged myoblasts through inhibition of glycogen synthase kinase or through overexpression of Wnt10b resulted in inhibition of adipogenic gene expression and sustained or enhanced myogenic differentiation. On the other hand, myoblasts isolated from Wnt10b null mice showed increased adipogenic potential, likely contributing to excessive lipid accumulation in actively regenerating myofibers in vivo in Wnt10b؊/؊ mice. Whereas Wnt10b deficiency contributed to increased adipogenic potential in myoblasts, the augmented myogenic differentiation potential observed is likely the result of a compensatory increase in Wnt7b during differentiation of Wnt10b؊/؊ myoblasts. No such compensation was apparent in aged myoblasts and in fact, both Wnt5b and Wnt10b were down-regulated. Thus, alteration in Wnt signaling in myoblasts with age may contribute to impaired muscle regenerative capacity and to increased muscle adiposity, both characteristic of aged muscle. INTRODUCTIONAdult skeletal muscle has remarkable regenerative capacity, largely mediated by satellite cells that reside between the sarcolemma and basal lamina of myofibers in postnatal muscle and remain throughout adult life (Bischoff, 1994). After muscle injury, satellite cells give rise to myoblasts that proliferate, migrate to the site of injury, and fuse into myofibers, thereby regenerating damaged or degenerating myofibers (Seale and Rudnicki, 2000). Deficits in the regenerative process occur as a function of age, some of which may be due to a decline in myoblast proliferative capacity (Schultz and Lipton, 1982;Dodson and Allen, 1987;Johnson and Allen, 1993;Renault et al., 2000) or to loss of factors required for satellite cell activity (Barton-Davis et al., 1998;Conboy et al., 2003). Although these deficits in myoblast activity may contribute to loss of muscle mass with age, they do not account for other features of aged muscle, in particular, increased lipid content . We previously showed that compared with myoblasts isolated from adult mice (8 mo), those isolated from the muscle of aged mice (23 mo) showed increased expression of genes normally restricted to the adipocyte lineage . Although genes involved in lipid trafficking and storage were overexpressed, a fully differentiated adipocyte phenotype is not achieved (Guan et al., 2002). Alteration of the expression and/or activity of peroxisome proliferator-activated receptor ␥ (PPAR␥) and CAAT/enhancer binding protein ␣ (C/EBP␣), both activators of adipocyte-specific genes (Tontonoz et al., 1994;Mandrup and Lane, 1997;Hamm et al., 2001), was appar...

Increased adipogenic conversion of muscle satellite cells in obese Zucker rats

“…25,41 Here, we show a significant lower wnt10b expression in the soleus muscle of obese (fa/fa) rats compared with controls (FA/FA) ( Figure 5). This reduction could contribute to the muscle mass decrease, besides the enhanced adipogenic potential of SCs, both observed in obese Zucker rats.…”

“…38,39 The Wnt signaling pathway, in particular the Wnt10b isoform, has a major role in adipogenesis of both preadipocytes and myogenic precursors in animals and humans. 16,24,25,40 In preadipocytes, wnt10b expression is remarkably elevated, thus contributing to preserve an undifferentiated state through the inhibition of c/ebpa and pparg expression. 23 Our data show a significantly lower expression of wnt10b in the SVF of obese Zucker rats that could promote an enhanced adipogenesis and justify a greater expansion of AT ( Figure 5).…”

“…Finally, because Wnt signaling is involved in both myogenic and adipogenic differentiation, [23][24][25] we compared wingless-type MMTV integration site family member 10b (wnt10b) expression in the muscle and AT of obese and lean rats taking into account the fiber composition (oxidative vs glycolytic) and AT cell fractions (mature adipocytes vs stromal cells).…”

Molecular mechanism of fatty degeneration in rotator cuff muscle with tendon rupture

“…These results indicate that Wnt10b plays a key role in the fatty degeneration of torn rotator cuff muscles. According to the increased adipogenic potential of myoblasts isolated from Wnt10b null mice, 18 it has been shown that Wnt10b suppresses adipogenic differentiation. The current research demonstrates for the first time that reduction of Wnt10b may be the molecular mechanism or one of the mechanisms of fatty degeneration in the rotator cuff muscles with torn tendons.…”

“…However, Wnt10b-ablated primary myoblasts showed increased myogenesis potential. 18 The molecular mechanism of muscle atrophy in rotator cuff tears may be different and may not involve Wnt10b. Further research will be required to reveal this mechanism.…”