Sex differences in human motor unit properties in response to simulated microgravity

Background: Establishing whether sex-specific differences exist in physiological responses to environmental insults, such as microgravity, is a major priority in modern physiology. With females now comprising 40% of current NASA astronauts, we still have a limited understanding of sex differences in adaptations to microgravity despite their increasing exposure to spaceflight. In this study, we compared electrophysiological changes in motor unit (MU) properties between males and females subjected to head-down tilt bed rest, a well-established experimental microgravity analog. Methods: Nine healthy young males (YM; 18–36 years) and nine healthy young females (YF; 18–31 years) underwent 21 days of −6° head-down tilt bed rest. Before and after bed rest, knee extensor maximal voluntary contraction (MVC) was assessed by isometric dynamometry, while vastus lateralis (VL) cross-sectional area (CSA) at 50% of femur length was evaluated by panoramic ultrasound. Intramuscular electromyography (iEMG) recordings were obtained from the VL to evaluate MU properties and neuromuscular junction (NMJ) transmission during voluntary contractions at 25% MVC. Statistical analysis was performed using linear mixed models (fixed effects: time and sex; cluster variable: subject). Results: Knee extensor MVC declined similarly in YM (−21.4%, p < 0.001) and YF (−22.3%, p < 0.001) following bed rest. VL CSA showed a parallel reduction (YM: −11.9%, p < 0.001; YF: −13.19%, p < 0.001). However, iEMG analysis revealed a significant sex × time interaction (p = 0.004) for motoneuron firing rate, with YF showing a greater decrease (−9.8%, p < 0.001) compared to YM (−5.1%, p < 0.001). Conversely, only YM showed a reduction in motor unit potential (MUP) area (−7.2%, p = 0.001), suggesting decreased MU size with disuse. Finally, impaired NMJ transmission, reflected by increased near fiber jiggle (+11.1%, p=0.036), was observed exclusively in YM. Conclusion: Despite a comparable loss of muscle strength and size, young males and females exhibit distinct neuromuscular adaptations to simulated microgravity. Females demonstrated greater central vulnerability, as indicated by the larger decline in motoneuron firing rate, whereas exclusively males showed signs of a more peripheral neuromuscular remodeling, as suggested by a reduced MU size and impaired NMJ transmission. These findings may be of considerable relevance for human health during spaceflight and may help guide the development of sex-specific countermeasures. Funding: This study was carried out within the framework of the collaboration agreement n. 2025-4-HB.0 between ASI and the University of Padua for the “Neuromyo” project. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.