Despite the prevalence and socioeconomic costs associated with conditions of muscle wasting, few treatment strategies for muscle atrophy have been identified. The Akt signaling pathway profoundly influences muscle growth, degradation and survival. In older animals, the activation of Akt and its downstream effectors is impaired in response to anabolic stimuli. We propose the direct activation of Akt may bypass age-related alterations in muscle that mediate this effect. Furthermore, we propose that proteins secreted from muscle participate in inter-tissue communication and that these regulatory mechanisms are diminished in elderly organisms where muscle mass is lost. Therefore, the proposed studies will test the hypothesis that acute genetic activation of Akt signaling in older (24 month) and middle-aged (12 month) mice will reverse, at least in part, age-associated decreases in strength, activity and metabolism to levels observed in young (4 month) mice. Related experiments will test whether the loss of Akt1 or Akt2 signaling in knockout mice will exacerbate the aging muscle phenotype in middle-aged and older mice. Other experiments will test the hypothesis that the age-dependent decline in the production of the muscle secreted protein follistatin-like 1 (Fstl1), i.e. a "myokine", will contribute to the age-dependent abnormalities in muscle function and regeneration.
This aim will examine the Akt-, injury- and age-dependent regulation of Fstl1 in muscle and characterize genetic gain- and loss-of- function models to understand the role of Fstl1 in basal muscle phenotype and regeneration in injury models.
Despite the prevalence and socioeconomic costs associated with conditions of muscle wasting, few treatment strategies for muscle atrophy have been identified. The Akt signaling pathway profoundly influences muscle growth, degradation and survival. Whereas previous studies have shown that reductions in Akt-associated signaling correlate with muscle age and type IIb fiber loss, the proposed studies will provide causal evidence that modulation of this signaling step will impact the phenotype of aging muscle.
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