Hindlimb unloading: rodent analog for microgravity

Abstract

The rodent hindlimb unloading (HU) model was developed in the 1980s to make it possible to study mechanisms, responses, and treatments for the adverse consequences of spaceflight. Decades before development of the HU model, weightlessness was predicted to yield deficits in the principal tissues responsible for structure and movement on Earth, primarily muscle and bone. Indeed, results from early spaceflight and HU experiments confirmed the expected sensitivity of the musculoskeletal system to gravity loading. Results from human and animal spaceflight and HU experiments show that nearly all organ systems and tissues studied display some measurable changes, albeit sometimes minor and of uncertain relevance to astronaut health. The focus of this review is to examine key HU results for various organ systems including those related to stress; the immune, cardiovascular, and nervous systems; vision changes; and wound healing. Analysis of the validity of the HU model is important given its potential value for both hypothesis testing and countermeasure development.

Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

“…It was also found that there were significant decreases in the absolute mass of gastrocnemius and quadriceps muscles, increases in atrogenes, MuRF1 and Atrogin‐1, and a significant decrease in muscle protein synthesis on days 7 to 14 . There are numerous other reports in the literature reporting significant bone and muscle loss with the hindlimb‐suspension model with as little as 14‐day suspension …”

“…The pieces of tape were attached to a string used to suspend the mice to a metal bar across the top of the cage. Strings were adjusted to support the mouse at approximately 30 degrees of elevation, which has been previously described as adequate elevation for consistent hindlimb unloading while avoiding unnecessary strain on the animals . The mice were housed two mice per cage; however, the tethering system of the hindlimb‐suspension cage prevented physical contact between the animals.…”

Muscle unloading: A comparison between spaceflight and ground‐based models

“…However, to bypass the ethical and logistical issues associated with human model, a rodent model was developed in 1970s in which hindlimbs are suspended in the air to simulate microgravity while forelimbs are weight bearing . This condition results in cephalic fluid shift and unloading of the hindlimbs (hindlimb unloaded model; HU), which mimic microgravity‐induced muscle loss . Furthermore, the HU model facilitates manipulations and interventions without extensive precautionary measures required for space‐based experiments .…”

“…Typically, the HU rodents are killed 15‐60 minutes after reloading, whereas the spaceflight rodents were killed 8‐11 hours after landing on earth. Prolonged time span between reloading and tissue collection might mitigate or mask some of the spaceflight effects . Furthermore, the skeletal muscles of humans, mice and rat differ in their contractile properties.…”

“…However, it seems that muscle function rather than fibre type plays a larger role in susceptibility to microgravity. Despite these differences, the ground‐based models have provided valuable information about the physiological changes that occur in conditions of microgravity …”