Possible involvement of p60-S6K1 in accelerating RPS6 phosphorylation for rapid recovery from skeletal muscle disuse atrophy.

Background: Stroke-prone spontaneously hypertensive rats (SHRSP) exhibit slow-twitch muscle-specific hypotrophy compared with normotensive Wistar-Kyoto rats (WKY). Because slow-twitch muscles are prone to disuse atrophy, SHRSP may experience both disuse atrophy and impaired recovery from it. This study investigated the response of SHRSP to disuse atrophy and subsequent recovery, using WKY as a control.

Results: WKY and SHRSP were subjected to a 7-day tail suspension followed by reloading for 1, 3, and 7 days. The soleus of WKY and SHRSP showed similar atrophic rates following tail suspension; however, the recovery after reloading was delayed in SHRSP. Moreover, WKY, but not SHRSP, exhibited sarcomere structure disruption after tail suspension, followed by necrosis, inflammatory cell infiltration, and edema upon reloading. Phosphorylation of ribosomal protein S6 (RPS6), an indicator of protein translation, was significantly higher in tail-suspended WKY-but not SHRSP-than those in non-tail-suspended groups after reloading. p70-S6 kinase 1 (S6K1), an upstream protein of RPS6, was phosphorylated at Thr389 in a mechanistic target of rapamycin complex 1-dependent manner to the same extent in both WKY and SHRSP; however, the expression of p60-S6K1-a shorter isoform of p70-S6K1 that activates RPS6 without p60-S6K1 phosphorylation-significantly increased only in tail-suspended WKY compared with those in non-tail-suspended WKY and tail-suspended SHRSP. Previously, p60-S6K1 protein expression was thought to result from an alternative translation of the full-length S6K1 transcript that also produces other S6K1 isoforms. However, recent studies have identified a p60-S6K1-specific transcript, and our PCR results showed that this p60-S6K1-specific transcript, but not the full-length S6K1 transcript, was significantly increased only in tail-suspended WKY corresponding with the increase of p60-S6K1 protein expression.

Conclusions: SHRSP exhibited different phenotypes in disuse atrophy and recovery from it compared with WKY, which could be related to suppressed RPS6 phosphorylation associated with the lack of upregulation in p60-S6K1 expression. These findings suggest that p60-S6K1, in cooperation with p70-S6K1, activates RPS6 and promotes rapid recovery from disuse atrophy by enhancing the transcription of the p60-S6K1-specific transcript. The study also suggests a potential involvement of hypertension in disuse atrophy and its recovery.