Partial weight suspension: a novel murine model for investigating adaptation to reduced musculoskeletal loading

Abstract

We developed a new model of hypodynamic loading to support mice in chronic conditions of partial weight bearing, enabling simulations of reduced gravity environments and related clinical conditions. The novel hardware allows for reduced loading between 10 and 80% of normal body weight on all four limbs and enables characteristic quadrupedal locomotion. Ten-week-old female BALB/cByJ mice were supported for 21 days under Mars-analog suspension (38% weight bearing) and compared with age-matched and jacketed (100% weight bearing) controls. After an initial adaptation, weight gain did not differ between groups, suggesting low levels of animal stress. Relative to age-matched controls, mice exposed to Mars-analog loading had significantly lower muscle mass (-23% gastrocnemius wet mass, P < 0.0001); trabecular and cortical bone morphology (i.e., trabecular bone volume: -24% at the distal femur, and cortical thickness: -11% at the femoral midshaft, both P < 0.001); and biomechanical properties of the femoral midshaft (i.e., -27% ultimate moment, P < 0.001). Bone formation indexes were decreased compared with age-matched full-weight-bearing mice, whereas resorption parameters were largely unchanged. Singly housed, full-weight-bearing controls with forelimb jackets were largely similar to age-matched, group-housed controls, although a few variables differed and warrant further investigation. Altogether, these data provide strong rationale for use of our new model of partial weight bearing to further explore the musculoskeletal response to reduced loading environments.

Mechanical regulation of signaling pathways in bone

“…Unloaded models have shown the rapid loss of bone in the affected limb, as well as adipogenesis within the bone marrow stem cell population, indicating reduced MSCs and greater marrow adiposity (Meyers et al, 2005). In an attempt to simulate reduced gravity environments more relevant to clinical conditions, a partial weight suspension model has recently been developed to allow investigation of adaptation to reduced skeletal loading (Wagner et al, 2010). This model has advantages over hind limb unloading conditions by creating a less stressful physical environment for the animal while generating similar losses in bone mineral and bone structure.…”

Biological effects of space radiation and development of effective countermeasures

“…Thus, several experiments have been performed to determine the effects of simulated microgravity on blood cell counts with or without additional exposure to space radiation [e.g., (148)]. To evaluate the impact of hypogravity on the effect of SPE radiation on immunological function, experiments were performed with 6–8 week old female ICR mice that were irradiated with 0.5, 1 or 2 Gy of γ-rays with or without hypogravity simulated using the PWS model, described by Wagner et al (149). The combination treatment with PWS and γ-ray irradiation decreased total splenic lymphocyte viability in a dose dependent manner, and the suppressed splenic lymphocyte viability in groups exposed to a 2 Gy dose of radiation persisted for 4 days, which was the last time point evaluated in the study (136).…”

Combined Effects of Botulinum Toxin Injection and Hind Limb Unloading on Bone and Muscle

“…Rodent disuse models can roughly be divided into two categories: 1) those that remove or reduce external ground reaction forces but spare muscle activation (e.g., hindlimb unloading (HLU) [5], limb immobilization [6], cast immobilization [7], partial weight suspension [8]), and 2) those that eliminate muscle contractions but permit external forces (e.g., botulinum toxin [9], neurectomy [10], tendon resection [11]). Although these two categories are useful for generally characterizing the disuse models, it is clear that the in vivo situation is more complex than implied by these two broad categories.…”