Prof Marco Narici
Department of Biomedical Sciences
University of Padova
Padova, Italy

Neuromuscular impairment in simulated hypogravity

Marco V. Narici^1,2, Evgeniia Motanova¹, Fabio Sarto¹, Giovanni Martino¹, Ornella Caputo¹, Martino Franchi¹, Uroš Marúsič², Giuseppe De Vito¹, Bostjan Siminič², Bruno Grassi³, Gianni Biolo⁴ and Rado Pišot²

¹Department of Biomedical Sciences, University of Padua, Italy;
²Science and Research Centre Koper, Slovenia;
³Department of Medicine, University of Udine, Udine, Italy;
⁴Department of Medical Sciences, University of Trieste, Italy

Chronic exposure to actual and simulated spaceflight profoundly affects the structural and functional integrity of the neuromuscular system1. Studies have shown that even short periods of unloading in simulated hypogravity can lead to loss of muscle mass, strength, as well as gene expression1, which are associated with significant neuromuscular alterations.

After just 3 days of unloading by dry-immersion, Demangel et al.2 reported significant muscle atrophy and force loss of the knee extensors associated by muscle fibre denervation.

Within ten days, signs of neuromuscular junction (NMJ) instability, altered NMJ morphology, extensive acetylcholine receptor remodelling, denervation, and axonal damage are observed3, 4. These changes result in altered motor unit recruitment threshold, reduced firing frequency, decreased conduction velocity, reduced neuromodulatory contribution by monoaminergic neurotransmitters5 (fundamental for setting the gain of spinal motor neurons excitability), and impaired NMJ transmission7, collectively leading to a loss of muscle strength and power exceeding what predicted by muscle atrophy alone5,6,7.

Recent evidence suggests that mitochondrial dysfunction, both near the NMJ in skeletal muscle fibers and within motor neuron terminals, may be a key factor responsible for NMJ instability and muscle denervation. Motanova et al.8, in a 10-day bed rest study, demonstrated that NMJ remodelling, characterised by decreased overlap between presynaptic and postsynaptic NMJ terminals, likely impairs NMJ transmission and signal propagation. Our data suggest that these changes are driven by oxidative stress, increased mitochondrial fission, and decreased mitochondrial volume density, ultimately triggering denervation and contributing to the loss of muscle strength and power observed in simulated hypogravity.

References:

• Pišot R. et al. (2016). J Appl Physiol., 120(8):922-9.
• Cam, F. et al. (2007). Journal of Applied Physiology, 102(6), 2315–2321.
• Demangel, R. et al. (2017). J Physiol, 595(13), 4301–4315.
• Monti, E. et al. (2021). Journal of Physiology, 599(12), 3037-3061
• Martino G. et al. (2024). Med Sci Sports Exerc., 56(9):1830-1839.
• Marusic U. et al. (2021). J Appl Physiol., 131(1):194-206.
• Sarto, F. et al. (2022). Journal of Physiology, 600(21), 4731-4751.

Motanova et al. (2025). J Physiol (In press)