Simulated space radiation sensitizes bone but not muscle to the catabolic effects of mechanical unloading

Abstract

Deep space travel exposes astronauts to extended periods of space radiation and mechanical unloading, both of which may induce significant muscle and bone loss. Astronauts are exposed to space radiation from solar particle events (SPE) and background radiation referred to as galactic cosmic radiation (GCR). To explore interactions between skeletal muscle and bone under these conditions, we hypothesized that decreased mechanical load, as in the microgravity of space, would lead to increased susceptibility to space radiation-induced bone and muscle loss. We evaluated changes in bone and muscle of mice exposed to hind limb suspension (HLS) unloading alone or in addition to proton and high (H) atomic number (Z) and energy (E) (HZE) (16O) radiation. Adult male C57Bl/6J mice were randomly assigned to six groups: No radiation ± HLS, 50 cGy proton radiation ± HLS, and 50 cGy proton radiation + 10 cGy 16O radiation ± HLS. Radiation alone did not induce bone or muscle loss, whereas HLS alone resulted in both bone and muscle loss. Absolute trabecular and cortical bone volume fraction (BV/TV) was decreased 24% and 6% in HLS-no radiation vs the normally loaded no-radiation group. Trabecular thickness and mineral density also decreased with HLS. For some outcomes, such as BV/TV, trabecular number and tissue mineral density, additional bone loss was observed in the HLS+proton+HZE radiation group compared to HLS alone. In contrast, whereas HLS alone decreased muscle mass (19% gastrocnemius, 35% quadriceps), protein synthesis, and increased proteasome activity, radiation did not exacerbate these catabolic outcomes. Our results suggest that combining simulated space radiation with HLS results in additional bone loss that may not be experienced by muscle.

Soluble RANKL exaggerates hindlimb suspension-induced osteopenia but not muscle protein balance

“…This difference in phosphorylation of downstream targets of mTOR is likely due to mTOR having a higher affinity to S6K1 and S6 than 4E-BP1 41 . These results confirm our previous work that showed muscle atrophy in response to HLS was mediated by a reduction in mTOR activity 9,10,23 . The injection of RANKL had no effect on muscle mass, protein synthesis, or mTOR activity.…”

“…As we were able to induce greater bone loss in the same time period in the present study, such data would support the idea that muscle and bone are not as integrally connected in their response to unloading as originally believed. Krause et al 23…”

“…We used a modified version of the HLS model first described by Morey-Holton and Globus 22 and previously described by our laboratory 10,23 . Mice were anesthetized with isoflurane (2% in O 2 ; Phoenix Pharmaceuticals, Inc.; Burlingame, CA) and two strips of bandage tape braided around the tail, secured to a swivel fishhook attached to a string.…”

Mechanical Loading Recovers Bone but not Muscle Lost During Unloading

“…These data suggest a delayed response of cortical bone to unloading that has not been previously reported. Our findings confirm previous studies from our group demonstrating that two weeks of HLS does not alter cortical outcomes compared to GC measured immediately following unloading [24]. However, in other studies we have demonstrated that three weeks of HLS does result in additional cortical bone loss [23,25], indicating that cortical bone is less responsive to unloading than trabecular bone.…”

“…We used a modified model of HLS originally described by Morey-Holton and Globus [27], and previously reported by our lab [23][24][25]. Mice were anesthetized with isoflurane (2% + oxygen) and a baseline microCT scan was performed prior to HLS.…”