Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice

Toro, C. A.; De Gasperi, R.; Aslan, A.; Johnson, N.; Siddiq, M. M.; Chow, C.; Zhao, W.; Harlow, L.; Graham, Z. A.; Liu, X.-H.; Sadoshima, J.; Iyengar, R.; Cardozo, C. P.

doi:10.1101/2023.08.04.551985

bioRxiv · 10.1101/2023.08.04.551985

Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice

Toro, C. A.·De Gasperi, R.·Aslan, A.·Johnson, N.·Siddiq, M. M.·Chow, C.·Zhao, W.·Harlow, L.·Graham, Z. A.·Liu, X.-H.·Sadoshima, J.·Iyengar, R.·Cardozo, C. P.

View original source ↗Export metadata ↓

Abstract

Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force due to reduced binding of calstabin 1 to RyR1 together with altered gating of RyR1. One cause of RyR1 oxidation is NADPH oxidase 4 (Nox4). We have previously shown that in rats, RyR1 was oxidized and bound less calstabin 1 at 56 days after spinal cord injury (SCI) by transection. Here, we used a conditional knock-out mouse model of Nox4 in muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force in control mice after SCI was reduced by 42% compared to sham-operated controls but was increased by approximately 43% in SCI Nox4 conditional KO mice compared to SCI controls although it remained less than that for sham-operated controls. Unlike what observed in rats, after SCI the expression of Nox4 was not increased in gastrocnemius muscle and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest a link between Nox4 expression in muscle tissue and reduction in muscle twitch force, however further studies are needed to understand the mechanistic basis for this linkage.

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Toro, C. A., De Gasperi, R., Aslan, A., Johnson, N., Siddiq, M. M., Chow, C., Zhao, W., Harlow, L., Graham, Z. A., Liu, X.-H., Sadoshima, J., Iyengar, R., Cardozo, C. P.. 2023-08-04. Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice. https://doi.org/10.1101/2023.08.04.551985

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Skeletal muscle aging drives sex- and compartment-specific protein insolubility that is modifiable by proteostasis-directed treatments

Protein aggregation and altered protein solubility indicate proteostatic decline, yet their roles in skeletal muscle aging remain poorly understood. We combined light and electron microscopy, quantitative proteomics, and stable-isotope labeling of skeletal muscle to investigate age-associated changes in protein insolubility, and their responses to exercise and rapamycin. Aged muscle accumulated distinct aggresome and amyloid-positive aggregates despite unchanged bulk insoluble protein content. Instead, aging altered the abundance and soluble-insoluble shifts of lower-abundance proteins across cellular components, particularly mitochondrial, nuclear and extracellular matrix proteins, with greater changes in females. These changes were not broadly explained by intrinsic protein aggregation propensity. Exercise and rapamycin partially reversed age-associated changes in abundance and partitioning without increasing protein synthesis. Together, these findings highlight sex- and cellular component-dependent changes in protein insolubility as important, modifiable aspects of skeletal muscle proteostasis, and indicate that proteostatic maintenance may be a more important target than anabolism for muscle aging.

physiology↗

bioRxiv2026

Trunk muscle activity across various trunk-limb coordination patterns in centipede locomotion

Animals coordinate movements of their limbs and flexible bodies, yet how trunk muscle activity changes across locomotor patterns remains unclear. We simultaneously recorded electromyograms from trunk muscles (deep dorsal oblique muscles) and trunk-limb kinematics in two centipede species exhibiting retrograde and direct locomotor waves during swimming and walking. During swimming, trunk muscle activity followed a similar phase relationship with trunk bending in both species despite opposite wave directions and different involvement of limbs, suggesting common active generation of undulation. During fast walking, trunk muscle activity was strongest around the ipsilateral swing phase in the undulatory retrograde-wave gait of Scolopendra mutilans, but weaker and associated with the ipsilateral stance phase despite the nearly straight trunk in the direct-wave gait of Scolopocryptops rubiginosus. Together, our findings suggest that the same trunk muscles serve two contrasting mechanical roles depending on locomotor mode: either generating trunk undulation or actively straightening the trunk against limb-induced deformation.

physiology↗

bioRxiv2026

Quantifying and Visualizing the Invisible Hazard of Infant Rebreathing

BACKGROUND: Rebreathing of expired gases during prone infant sleeping contributes to hypoxic and hypercapnic exposure, even without airway obstruction. We investigated how anatomical, physiological, and environmental factors influence aerodynamic rebreathing. METHODS: A dynamically scaled in vitro model simulated prone nasal breathing corresponding to infants weighing 2 to 5 kg, with nostril diameters of 3.2 to 6.0 mm and breathing frequencies of 25 to 40 breaths/min. Ambient temperature and sleep-surface characteristics were varied. Rebreathing was quantified using tracer measurements, while flow visualization revealed the underlying aerodynamic mechanisms. RESULTS: Rebreathing exceeded 60% despite unobstructed nasal openings. Increasing ambient temperature from 23 to 30 degrees C increased rebreathing by 68 to 77%, while reducing simulated infant mass from 5 to 2 kg increased rebreathing by 39 to 46%. Fibrous surfaces increased rebreathing, particularly near inclined nasal openings. A novel finding was that increasing nostril diameter from 3.2 to 6.0 mm increased rebreathing by up to 50%. Flow visualization revealed vortical structures that retained expired fluid near the nasal openings, facilitating re-inspiration. CONCLUSIONS: Aerodynamic rebreathing depends strongly on simulated infant characteristics and sleeping environments. These findings are consistent with established safe-sleep recommendations and identify nostril diameter, for the first time, as a potentially important anatomical factor warranting clinical investigation.

physiology↗