The Effect of Irradiation on Akt Signaling in Atrophying Skeletal Muscle

Muscle irradiation (IRR) exposure can accompany unloading during spaceflight or cancer treatment, and this has been shown to be sufficient by itself to induce skeletal muscle signaling associated with a remodeling response. While protein kinase B/Akt has an established role in the regulation of muscle growth and metabolism, there is a limited understanding of how Akt signaling in unloaded skeletal muscle is affected by IRR. Therefore, we examined the combined effects of acute IRR and short-term unloading on muscle Akt signaling. Female C57BL/6 mice were subjected to load bearing or hindlimb suspension (HS) for 5 days (N=6/group). A single, unilateral hindlimb IRR dose (0.5 Gy X-ray) was administered on day 3. Gastrocnemius muscle protein expression was examined. HS decreased Akt^T308 phosphorylation, while HS+IRR increased AktT308 phosphorylation above baseline. HS reduced Akt^S473 phosphorylation, which was rescued by HS+IRR. Interestingly, IRR alone increased AktS⁴⁷³, but not AktT308, phosphorylation. HS decreased mTORC1 signaling, and this suppression was not altered by IRR. Both IRR and HS increased MuRF-1 expression, while Atrogin-1 expression was not affected by either condition. These results demonstrate IRR alone or when combined with HS can differential affect Akt phosphorylation, but IRR did not disrupt suppressed mTORC1 signaling by HS. Collectively, these findings highlight that a single IRR dose is sufficient to disrupt the regulation of Akt signaling in atrophying skeletal muscle.

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