Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle.

The intent of this study was to determine whether aging affects signaling pathways involved in mitochondrial biogenesis in response to a single bout of contractile activity. Acute stimulation (1 Hz, 5 min) of the tibialis anterior (TA) resulted in a greater rate of fatigue in old (36 month), compared to young (6 month) F344XBN rats, which was associated with reduced ATP synthesis and a lower mitochondrial volume. To investigate fiber type-specific signaling, the TA was sectioned into red (RTA) and white (WTA) portions, possessing two- to 2.5-fold differences in mitochondrial content. The expression and contraction-mediated phosphorylation of p38, MKK3/6, CaMKII and AMPKalpha were assessed. Kinase protein expression tended to be higher in fiber sections with lower mitochondrial content, such as the WTA, relative to the RTA muscle, and this was exaggerated in tissues from senescent, compared to young animals. At rest, kinase activation was generally similar between young and old animals, despite the age-related variations in mitochondrial volume. In response to contractile activity, age did not influence the signaling of these kinases in the high-oxidative RTA muscle. However, in the low-oxidative WTA muscle, contraction-induced kinase activation was attenuated in old animals, despite the greater metabolic stress imposed by contractile activity in this muscle. Thus, the reduction of contraction-evoked kinase phosphorylation in muscle from old animals is fiber type-specific, and depends on factors which are, in part, independent of the metabolic milieu within the contracting fibers. These findings imply that the downstream consequences of kinase signaling are reduced in aging muscle.