It is unknown whether loss of skeletal muscle mass and function experienced by astronauts during space flight could be augmented by ionizing radiation (IR), such as low-dose high-charge and energy (HZE) particles or low-dose high-energy proton radiation. In the current study adult mice were irradiated whole-body with either a single dose of 15 cGy of 1 GeV/n 56Fe- particle or with a 90 cGy proton of 1 GeV/n proton particles. Both ionizing radiation types caused alterations in the skeletal muscle cytoplasmic Ca 2+ (Ca2+i) homeostasis. 56Fe-particle irradiation also caused a reduction of depolarization-evoked Ca2+ release from the sarcoplasmic reticulum (SR). The increase in the Ca 2+i was detected as early as 24 h after 56Fe-particle irradiation, while effects of proton irradiation were only evident at 72 h. In both instances Ca2+i returned to baseline at day 7 after irradiation. All 56Fe-particle irradiated samples revealed a significant number of centrally localized nuclei, a histologic manifestation of regenerating muscle, 7 days after irradiation. Neither unirradiated control or proton-irradiated samples exhibited such a phenotype. Protein analysis revealed significant increase in the phosphorylation of Akt, Erk1/2 and rpS6k on day 7 in 56Fe-particle irradiated skeletal muscle, but not proton or unirradiated skeletal muscle, suggesting activation of pro-survival signaling. Our findings suggest that a single low-dose 56Fe-particle or proton exposure is sufficient to affect Ca2+ homeostasis in skeletal muscle. However, only 56Fe-particle irradiation led to the appearance of central nuclei and activation of pro-survival pathways, suggesting an ongoing muscle damage/recovery process.