DT, Roberts MD. Cross talk between androgen and Wnt signaling potentially contributes to age-related skeletal muscle atrophy in rats. We sought to determine whether age-related gastrocnemius muscle mass loss was associated with parallel decrements in androgen receptor (AR) or select Wnt signaling markers. To test this hypothesis, serum-free and total testosterone (TEST) and gastrocnemius AR and Wnt signaling markers were analyzed in male Fischer 344 rats that were 3, 6, 12, 18, and 24 mo (mo)

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... d (n ϭ 9 per group). Free and total TEST was greatest in 6 mo rats, and AR protein and Wnt5 protein levels linearly declined with aging. There were associations between Wnt5 protein levels and relative gastrocnemius mass (r ϭ 0.395, P ϭ 0.007) as well as AR and Wnt5 protein levels (r ϭ 0.670, P Ͻ 0.001). We next tested the hypothesis that Wnt5 affects muscle fiber size by treating C2C12derived myotubes with lower (75 ng/ml) and higher (150 ng/ml) concentrations of recombinant Wnt5a protein. Both treatments increased myotube size (P Ͻ 0.05) suggesting this ligand may affect muscle fiber size in vivo. We next tested if Wnt5a protein levels were androgen-modulated by examining 10-mo-old male Fischer 344 rats (n ϭ 10 -11 per group) that were orchiectomized and treated with testosterone-enanthate (TEST-E); trenbolone enanthate (TREN), a nonaromatizable synthetic testosterone analogue; or a vehicle (ORX only) for 4 wk. Interestingly, TEST-E and TREN treatments increased Wnt5a protein in the androgen-sensitive levator ani/bulbocavernosus muscle compared with ORX only (P Ͻ 0.05). To summarize, aromatizable and nonaromatizable androgens increase Wnt5a protein expression in skeletal muscle, age-related decrements in muscle AR may contribute Wnt5a protein decrements, and our in vitro data imply this mechanism may contribute to age-related muscle loss. NEW & NOTEWORTHY Results from this study demonstrate androgen and Wnt5 protein expression decrease with aging, and this may be a mechanism involved with age-related muscle loss.