Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

Abstract

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

αKlotho decreases after reduced weight-bearing from both spaceflight and hindlimb unloading

“…This pilot investigation measured circulating αKlotho levels in mice after exposure to two reduced weight-bearing conditions: microgravity aboard the ISS, and after hind limb unloading (HU) 13 . Importantly, musculoskeletal degradation has previously been described in hindlimbs from these same mice after 35 days in microgravity and HU 14 , 15 , observing recovery of joint health upon return to full weight-bearing with exercise 15 . Likewise, this study examined if deficits in circulating αKlotho after periods HU could be recovered after return to full-weight bearing, with/without performing exercise.…”

“…For HU mice, levels of αKlotho increased following exercise, with partial recovery in the running group and full recovery in the climbing group, suggesting an important relationship between exercise/potentially elevated weight-bearing and αKlotho level improvement. These data are aligned with recovery of joint health upon a return to full weight-bearing with exercise 15 . Moreover, for FLIGHT mice, where muscle masses were collected, the decrease in αKlotho post-flight occurred with reduced gastrocnemius mass, which itself is not unexpected but αKlotho may also be affected by skeletal muscle activity 18 .…”

“…The animal and environmental details of the ISS study (Rodent Research-9 mission), the accompanying HU study, and all approved IACUC protocols from Wake Forest School of Medicine, NASA Ames, and the Kenney Space Center have been published 15 . All mice were male, C57BL/6 (Jackson Labs) that were 10 weeks at the start of each study.…”

“…Groups included FLIGHT and GROUND control 15 . This investigation had access to n = 4–5 plasma samples/group collected after 35 days on orbit; all available samples were analyzed for this study.…”

Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight

“…The primary muscles in the human body are the muscles of the upper limb and lower limb. Experiments on hind limb muscle wasting after a 13-day shuttle flight have shown reduced knee weight bearing and meniscal degradation, inducing an arthritic phenotype in cartilage and menisci [ 2 ]. Changes in electrical impedance characteristics in gastrocnemius muscles are also induced by spaceflight [ 3 ].…”