Disuse Atrophy

Disuse atrophy is the loss of muscle protein, cross-sectional area and force that follows removal of mechanical loading. In humans the dominant driver is a fall in muscle protein synthesis rather than a surge in breakdown, and it appears within days: both the fasted synthetic rate and the response to dietary protein are blunted, a state usually called anabolic resistance. This is a genuine species difference. Rodent hindlimb suspension and denervation models are dominated by the ubiquitin-proteasome pathway through the atrogenes MuRF1 and atrogin-1, and human unloading studies show far less of that signal.

The magnitudes are consistent across the bed rest, casting and spaceflight literature. Leg lean mass falls on the order of half a percent per day in the early phase, and a single week of immobilisation costs a few percent of quadriceps cross-sectional area. Strength falls faster than mass, because much of the early loss is neural rather than contractile.

The therapeutic history is the reason to distrust mass-based endpoints. Myostatin pathway inhibitors, including bimagrumab and several antibodies against myostatin itself, reliably increased lean mass in humans and then repeatedly failed to convert it into function. Bimagrumab missed its primary endpoint in the RESILIENT trial in sporadic inclusion body myositis despite increasing thigh muscle volume.

The gap worth stating plainly is that no peptide marketed for preventing or reversing disuse atrophy has been tested in a controlled human immobilisation or bed-rest study. The supporting material is rodent unloading data, from the very model that overweights the proteolytic mechanism humans use least, plus the observation that growth hormone axis agents improve nitrogen retention, which is a measure of balance rather than strength.