Biology subjects

Jackson, M. J.

Publications and source records attributed to Jackson, M. J..

6 recordsLinked to original sources

bioRxiv2026

MicroAge Mission: Effects of Microgravity and Heat Shock Protein 10 Overexpression on the Proteome of Human Tissue-Engineered Muscle Constructs - Implications for Skeletal Muscle Ageing

Age-related loss of skeletal muscle mass and function, or sarcopenia, presents a growing clinical challenge, mirroring the accelerated muscle atrophy seen in microgravity. This study, part of the UK Space Agencys MicroAge Mission, aimed to investigate microgravity-induced proteomic changes in 3D human skeletal muscle constructs and assess whether mitochondrial Heat Shock Protein 10 (HSP10) overexpression could modulate these responses. Constructs derived from control human AB1167 myoblasts and AB1167 myoblasts that were transduced to overexpress HSP10, were flown to the International Space Station (ISS), with a ground reference experiment (GRE) conducted post-flight. Proteomic analysis using mass spectrometry and bioinformatics revealed significant alterations in metabolic, structural, and mitochondrial protein profiles after microgravity exposure. Microgravity caused downregulation of key proteins involved in energy metabolism, stress responses and structural integrity, while upregulating catabolic and apoptotic enzymes. Many of these modifications parallel previously reported changes in protein composition of muscle with ageing on earth. Overexpression of HSP10 attenuated the effects of microgravity, with fewer proteins showing significant changes and reduced disruption to mitochondrial and cytoskeletal components. Pathway analysis indicated that HSP10 overexpression preserved mitochondrial protein expression, particularly in the matrix, and promoted mitochondrial gene expression and translation under microgravity conditions. Notably, 284 proteins altered by microgravity in unmodified muscle constructs remained stable in HSP10-overexpressing constructs, suggesting a protective effect. MitoCarta 3.0 analysis confirmed that HSP10 expression modulated protein responses at the mitochondrial level, mitigating declines in bioenergetic proteins that are typically associated with microgravity. Collectively, the findings demonstrate that microgravity induces extensive proteomic remodelling in human muscle, which is partially offset by HSP10 overexpression. These results offer insights into muscle atrophy in spaceflight and suggest that targeting mitochondrial stress pathways via chaperone modulation may be a viable strategy to combat sarcopenia and disuse-induced muscle loss on Earth and in space.

physiology↗

bioRxiv2025

Age and Sex Influence Diurnal Memory Oscillations, Circadian Rhythmicity, and Per1 Expression

BackgroundThe circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression. MethodsWe used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice. ResultsYoung female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning- induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance. ConclusionsThis work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age. HighlightsO_LIDiurnal oscillations in spatial memory are sex- and age-dependent in mice C_LIO_LIPer1 learning-induced expression matches diurnal memory patterns C_LIO_LICircadian rhythm patterns are sex- and age-dependent in mice C_LIO_LIYoung females show good memory across the diurnal cycle C_LIO_LIDiurnal memory oscillations reemerge in old female mice C_LI Plain language summaryMemory is an integral part of everyday functioning, and one that is known to decline with aging. Our lab has previously shown that the clock gene Period1 (Per1) regulates spatial memory performance in young males, establishing a molecular link between circadian rhythms and memory. Young adult male mice show diurnal oscillations in memory consolidation, with the best memory occurring at midday, and the worst memory occurring at midnight. In the current study, we wanted to expand our work to young adult females, as well as an aged population of male and female mice. Using a simple spatial memory task, we measured diurnal changes in both memory performance and Per1 gene expression within the dorsal hippocampus (a brain region necessary for spatial memory). We found that old mice (both male and female) showed a correlation between high Per1 levels and better memory, as we have previously seen. Conversely, young female mice performed well on the memory task at every timepoint but didnt have a significant change in Per1, indicating that they may be using some different mechanism to modulate memory performance. Finally, we used infrared activity monitoring to investigate several circadian rhythm related measures in young and old, male and female mice. We found that sex influenced the circadian rhythm more than age, and the group with the largest circadian disruption was aged males. Overall, this research provides new information about how both sex and age impact diurnal oscillations in both memory and activity, fundamental knowledge that has been lacking in the field.

animal behavior and cognition↗

bioRxiv2025

MicroAge Mission: Experimental Design, Hardware Development and Operational Considerations for a Bespoke Culture System to Support Tissue-Engineered Skeletal Muscle Constructs.

Microgravity provides a unique model for understanding accelerated skeletal muscle loss, and potentially a model of muscle ageing, offering insights into the molecular mechanisms underlying reductions in muscle mass and function. During spaceflight, astronauts experience pronounced skeletal muscle atrophy. These effects appear similar to age-related muscle decline on Earth but on a significantly shorter timescale. Despite the incorporation of daily aerobic and resistance exercise on the International Space Station (ISS), countermeasures remain suboptimal, reflecting analogous challenges in exercise efficacy observed in ageing populations. The MicroAge Mission aimed to exploit microgravity conditions aboard the ISS to determine whether the molecular mechanisms underpinning reduced adaptive responses to contractile activity during ageing are analogous to those induced by spaceflight. The mission also explored proof-of-concept genetic interventions, including overexpression of Heat Shock Protein 10 (HSP10), a mitochondrial chaperone, to mitigate muscle atrophy and functional loss. To conduct these investigations, a tissue-engineering approach was employed to fabricate human skeletal muscle constructs, which were secured to custom-designed 3D-printed scaffolds. The scaffolds featured integrated microfluidic channels designed to interface with the fluid handling system within the flight hardware. The hardware, developed by Kayser Space Ltd, was specifically designed to interface with the European Space Agencys (ESA) Kubik incubator located within the Columbus module of the ISS. This research addresses critical methodological constraints in low Earth orbit (LEO) experimentation, providing a detailed account of pre-flight protocol development, muscle construct biofabrication techniques, and operational considerations. The findings establish a translational framework for future investigations into musculoskeletal degeneration, with implications for therapeutic strategies targeting both terrestrial ageing and astronaut musculoskeletal health.

bioengineering↗

bioRxiv2024

Peroxiredoxin 2 mediates redox-stimulated adaptations to oxidative phosphorylation induced by contractile activity in human skeletal muscle myotubes

Skeletal muscle generates superoxide during contractions, which is converted to hydrogen peroxide (H2O2). H2O2 has been proposed to activate signalling pathways and transcription factors that regulate adaptive responses to exercise, but the concentration required to oxidize and activate key redox-sensitive signalling proteins in vitro is much higher than the typical intracellular levels seen in muscle after exercise. We hypothesized that 2-Cys-peroxiredoxins (PRDX), which rapidly oxidize in the presence of physiological concentrations of H2O2, serve as intermediary signalling molecules and play a crucial role in activating adaptive pathways following muscle contractions. This study has examined the human muscle myotube responses to contractile activity, or exposure to low extracellular concentrations (2.5-5 {micro}M) of H2O2 and whether knock down of muscle PRDX2 alters the differential gene expression (DEG) that results from these stresses. Exposure of human skeletal muscle myotubes to a 15 min period of aerobic electrically stimulated isometric contractions or 5M H2O2 induced substantial changes in DEG with modification of many genes associated with adaptations of skeletal muscle to contractile activity. Common DEG in these conditions included upregulation of genes associated with increased mitochondrial oxidative phosphorylation, including COX1, COX2, COX3 and ATP6. In myotubes with PRDX2 knock down (94% decrease in PRDX2 mRNA), the upregulation of genes associated with increased mitochondrial oxidative phosphorylation was abolished following contractile activity or exposure to H2O2. These data indicate that a common effect of contractile activity and exposure to "physiological" levels of H2O2 in human myotubes is to increase the expression of multiple genes associated with increased mitochondrial oxidative phosphorylation. Furthermore, these effects were abolished in PRDX2 knock down myotubes indicating that adaptations to upregulate multiple genes related to increased mitochondrial capacity in human muscle myotubes in response to exercise is both redox regulated and requires PRDX2 as an essential mediator of the effects of H2O2.

physiology↗

bioRxiv2023

Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis

The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.

physiology↗

bioRxiv2022

Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice

Whole body knock out of Cu, Zn superoxide dismutase1 (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with a breakdown of neuromuscular junctions (NMJ) similar to sarcopenia. In order to determine whether altered redox in motor neurons is integral to this phenotype, an inducible neuron specific deletion of Sod1 (i-mnSod1KO) was compared with wild type (WT) mice of different ages (adult, mid-age and old) and whole body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined. Deletion of neuronal Sod1 (induced by tamoxifen injection at 6 months of age) caused the exaggerated, age-associated loss of muscle mass and force generation previously reported. No effect of age or lack of neuronal Sod1 was seen on oxidation in the sciatic nerve assessed by electron paramagnetic resonance of the in vivo spin probe 1-hydroxy-3-carboxy-2,2,5,5 tetramethylpyrrolidine (CPH), analysis of protein 3-nitrotyrosines or carbonyl content. i-mnSod1KO mice showed increased numbers of denervated NMJs, a reduced number of large axons and increased number of small axons compared with age-matched old WT mice. A large proportion of the remaining innervated NMJs in i-mnSod1KO mice also displayed a much simpler structure than that seen in WT mice. Thus, while Sod1KO mice recapitulate substantially the neuromuscular phenotypes of old WT mice, deletion of Sod1 specifically in neurons induces exaggerated loss of muscle mass and force only in old (24-29 month) mice indicating that significant muscle declines require the accumulation of age-related changes such that a threshold is reached past which maintenance of structure and function is not possible. Significance statementSarcopenia is the age-related loss of muscle mass and function. It is a significant contributor to frailty and to increased falls in the elderly. While multifactorial, changes in redox status have been shown to have significant influence over neuromuscular aging, recent work suggests that changes in motor neurons may be the driving factor in muscle atrophy. The current study confirmed that a specific lack of Sod1 in the motor neuron causes significant alteration in axonal architecture and the neuromuscular junctions which can drive reduced muscle mass and function. Pinpointing early changes in motor neurons may provide therapeutic targets critical for maintaining muscle in the elderly.

physiology↗