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...

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SummaryMyogenic progenitors in adult muscle are necessary for the repair, maintenance and hypertrophy of post-mitotic muscle fibers. With age, fat deposition and fibrosis contribute to the decline in the integrity and functional capacity of muscles. In a previous study we reported increased accumulation of lipid in myogenic progenitors obtained from aged mice, accompanied by an up-regulation of genes involved in adipogenic differentiation. The present study was designed to extend our understanding of how aging affects the fate and gene expression profile of myogenic progenitors. Affymetrix murine U74 Genechip analysis was performed using RNA extracted from myogenic progenitors isolated from adult (8-month-old) and aged (24-month-old) DBA/2JNIA mice. The cells from the aged animals exhibited major alterations in the expression level of many genes directly or indirectly involved with the TGFβ β β β signaling pathway. Our data indicate that with age, myogenic progenitors acquire the paradoxical phenotype of being both TGFβ β β β activated based on overexpression of TGFβ β β β -inducible genes, but resistant to the differentiation-inhibiting effects of exogenous TGFβ β β β . The overexpression of TGFβ β β β -regulated genes, such as connective tissue growth factor, may play a role in increasing fibrosis in aging muscle.

Studies have been performed in humans to identify changes in gene expression that may account for the relatively weak and variable response of aged muscle to resistance exercise. The gene expression profile of skeletal muscle from elderly (62-75 years old) compared to younger (20-30 years old) men demonstrated elevated expression of genes typical of a stress or damage response. The expression of the majority of these genes was unaffected by a single bout of high-intensity resistance exercise in elderly subjects but was altered acutely by exercise in younger subjects so as to approach the pre-exercise levels observed in older subjects. The inability of muscle from elderly subjects to respond to resistance exercise was also apparent in the expression of inflammatory response genes, which increased within 24 hours of the exercise bout only in younger subjects. Othergenes with potentially important roles in the adaptation of muscle to exercise, showed a similar or even more robust response in older compared to younger subjects. Taken together, these results may help to explain the variable hypertrophic response of muscle from older individuals to resistance training.