Aaron Paul Russell

Understanding the mechanisms driving TDP-43 pathology is essential for combating amyotrophic lateral sclerosis and other neurodegenerative diseases. To investigate the contribution of skeletal muscle to disease onset, progression, and recovery, we generated an inducible, muscle-specific TDP-43 mouse model. Cytoplasmic aggregation of exgogenous human TDP-43 protein in skeletal muscle led to muscle dysfunction, denervation, motor neuron loss, and dysregulation of mRNA markers related to myogenesis and neuromuscular junction stress at disease early-stage, along with muscle atrophy, neurodegeneration, and fatal motor decline at disease late-stage. Notably, this endogenous TDP-43 propagated from skeletal muscle to the spinal cord and brain, underscoring the vulnerability of the central nervous system to muscle-derived TDP-43 toxicity. Suppression of cytoplasmic TDP-43 in skeletal muscle improved survival and promoted substantial recovery of muscle dysfunction, motor deficits and neurodegeneration. These findings highlight the therapeutic potential of targeting skeletal muscle-derived TDP-43 toxicity as an approach to delaying neurodegenerative disease.

This systematic review aimed to examine the chronic adaptations of blood flow restriction (BFR) in conjunction with aerobic and bodyweight resistance training. A search of the electronic databases PubMed (MEDLINE), CINAHL, SPORTDiscus® (via EBSCOhost), Embase, and Cochrane (Central) was conducted to identify relevant published studies. The inclusion criteria encompassed a healthy adult sample population (>18 years), original studies, chronic exercise training interventions (minimum 2 weeks duration) employing aerobic BFR exercise or bodyweight resistance BFR exercise, and comparisons with equivalent intensity non-BFR aerobic or bodyweight resistance training. Thirty-three (n = 33) studies met the inclusion criteria and were included in the review. Among the included studies, chronic adaptations to BFR aerobic training were characterized by significant improvements in aerobic capacity (4-9%), muscle strength (6-31%), and muscle hypertrophy (2-11%) compared to non-BFR aerobic training. Furthermore, bodyweight resistance BFR training increased muscle hypertrophy (3-5%) and strength (4-11%). The findings suggest that both aerobic and bodyweight BFR training provide interchangeable options for practitioners prescribing BFR without access to a traditional equipment filled training environment, supporting flexibility in exercise programme design tailored to individual preferences, facility constraints, and specific fitness goals.

This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3–4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.

Female carriers of a Duchenne muscular dystrophy ( DMD ) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT‐labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA‐binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post‐menopausal DMD carriers.

Purpose In young adults, the hormonal responses to resistance exercise are amplified by normobaric hypoxia. Hormone concentrations and metabolism are typically dysregulated with age, yet the impact of hypoxia on these responses to resistance exercise are uncharacterised. Therefore, this study aimed to characterise the acute and chronic hormonal and metabolic responses of older adults to resistance training in normobaric hypoxia. Methods Adults aged 60–75 years completed 8 weeks of resistance training in either normoxia (20.9% O₂; n = 10) or normobaric hypoxia (14.4% O₂, n = 10) twice weekly at 70% of their predicted 1-repetition maximum. Growth hormone, glucose, lactate, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), cortisol, total testosterone, adrenaline, noradrenaline and dopamine were quantified at pre- and post-training, and in the 60 min following the first training session (untrained state) and the last training session (trained state). Results Eight weeks of training in hypoxia did not affect the resting levels of the hormones or physiological factors measured. However, hypoxia significantly blunted the acute growth hormone response in the 15 min following the last training session at week eight (43.87% lower in the hypoxic group; p = 0.017). This novel and unexpected finding requires further investigation. All other hormones were unaffected acutely by hypoxia in the 60 min following the first and the last training session. Conclusion Chronic resistance training in normobaric hypoxia supresses the growth hormone response to exercise in older adults. All other hormones and metabolic markers were unaffected both acutely and chronically by hypoxia.

New Findings What is the central question of this study? Striated Muscle activator of Rho signalling (STARS) is an actin‐binding protein that regulates transcriptional pathways controlling muscle function, growth and myogenesis; processes impaired in dystrophic muscle. Regulation of the STARS pathway in Duchenne muscular dystrophy (DMD is unknown. What is the main finding and its importance? Members of the STARS signalling pathway are reduced in the quadriceps of patients with DMD and in mouse models of muscular dystrophy. Overexpression of STARS in the dystrophic deficient mdx mouse model increased maximal isometric specific force and upregulated members of the actin cytoskeleton and oxidative phosphorylation (OXPHOS) pathways. Regulating STARS may be a therapeutic approach to enhance muscle health. Abstract Duchenne muscular dystrophy (DMD) is characterized by impaired cytoskeleton organization, cytosolic calcium handling, oxidative stress and mitochondrial dysfunction. This results in progressive muscle damage, wasting and weakness and premature death. The Striated Muscle activator of Rho signalling (STARS) is an actin‐binding protein that activates the myocardin‐related transcription factor‐A (MRTFA)/serum response factor (SRF) transcriptional pathway; a pathway regulating cytoskeletal structure and muscle function, growth and repair. We investigated the regulation of the STARS pathway in the quadriceps muscle from patients with DMD and in the tibialis anterior (TA) muscle from the dystrophin‐deficient mdx and dko (utrophin and dystrophin null) mice. Protein levels of STARS, SRF and RHOA were reduced in patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in the mdx mice and Srf and Mrtfa mRNAs decreased in the dko mice. Overexpressing human STARS (hSTARS) in the TA muscles of mdx mice increased maximal isometric specific force by 13% (p<0.05). This was not associated with changes in muscle mass, fibre cross‐sectional area (CSA), fibre type, centralised nuclei or collagen deposition. Proteomics screening, followed by pathway enrichment analysis, identified that hSTARS overexpression resulted in 31 upregulated and 22 downregulated proteins belonging to the actin cytoskeleton and oxidative phosphorylation (OXPHOS) pathways. These pathways are impaired in dystrophic muscle and regulate processes that are vital for muscle function. Increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via synergistic regulation of cytoskeletal structure and energy production. This article is protected by copyright. All rights reserved

Skeletal muscle is sensitive to environmental cues that are first present in utero. Maternal overnutrition is a model of impaired muscle development leading to structural and metabolic dysfunction in adult life. In this study, we investigated the effect of an obesogenic maternal environment on growth and postnatal myogenesis in the offspring. Male C57BL/6J mice born to chow- or high-fat-diet-fed mothers were allocated to four different groups at the end of weaning. For the following 10 wk, half of the pups were maintained on the same diet as their mother and half of the pups were switched to the other diet (chow or high-fat). At 12 wk of age, muscle injury was induced using an intramuscular injection of barium chloride. Seven days later, mice were humanely killed and muscle tissue was harvested. A high-fat maternal diet impaired offspring growth patterns and downregulated satellite cell activation and markers of postnatal myogenesis 7 days after injury without altering the number of newly synthetized fibers over the whole 7-day period. Importantly, a healthy postnatal diet could not reverse any of these effects. In addition, we demonstrated that postnatal myogenesis was associated with a diet-independent upregulation of three miRNAs, mmu-miR-31–5p, mmu-miR-136–5p, and mmu-miR-296–5p. Furthermore, in vitro analysis confirmed the role of these miRNAs in myocyte proliferation. Our findings are the first to demonstrate that maternal overnutrition impairs markers of postnatal myogenesis in the offspring and are particularly relevant to today’s society where the incidence of overweight/obesity in women of childbearing age is increasing.