Differential effects of wheel running and treadmill exercise on spatial memory, adult hippocampal neurogenesis and the cerebrospinal fluid proteome in rats.

Evolutionarily conserved neural circuits evolved that mediate switching between feeding and foraging for food, depending on environmental conditions such as food scarcity and internal state [1-3]. Activity-based anorexia is a phenomenon observed ubiquitously in normal mammals that emerges under conditions of time-restricted food availability and continuous access to running wheels. Under these experimental conditions, rodents progressively lose body weight and develop paradoxical hypophagia and compulsive wheel running, which can prove fatal if left unchecked. On the other hand, rodents survive indefinitely under conditions of either time-restricted food access or running wheel availability. In this review, we discuss preclinical studies within the past decade which used modern genetic circuit-dissecting tools including chemogenetic, optogenetic, and calcium imaging, to dissect the neural circuitry modulating activity-based anorexia. We highlight how circuits interconnecting the hypothalamus, prefrontal cortex, amygdala, mesolimbic system, and monoaminergic nuclei, interact to modulate animals' decision to feed or forage in the activity-based anorexia paradigm. We then highlight how these recent findings have aided in identifying pathophysiological mechanisms underlying neuropsychiatric disorders characterized by the maladaptive prioritization of exercise over feeding. Finally, we suggest approaches for the development of targeted therapeutics for anorexia nervosa, which has no approved pharmacological treatments.

Post-traumatic joint contracture (PTJC) frequently occurs in the elbow after injury, decreasing range of motion (ROM) and causing dysfunction. Physical therapy improves ROM but does not address underlying inflammation and fibrosis. Combining physical exercise with biological treatment has shown positive results in other physiological systems. Objective: evaluate whether active physical therapy and anti-inflammatory drug treatment, alone or in combination, could preserve mechanics and function in a rat model of PTJC. Elbow PTJC was surgically induced in rats followed by joint immobilization (IM). Animals received either anti-inflammatory drug (celecoxib or CEL) treatment, active physical therapy (wheel activity or WA), or both (CELWA). An untreated cage activity (CA) group served as control. Functional evaluation, joint mechanical testing, and histological analysis were used to compare groups. All treatments improved gait parameters compared to CA, with WA showing the most improvements. WA also showed improved forelimb strength ratio compared to CA, but this difference was not significant. Postmortem joint mechanics were slightly improved in WA and CEL and most improved in CELWA compared to CA. Histological analysis showed that all treatments improved fibrosis, adhesions, vascularity, and thickness of capsule tissue to varying degrees. Cartilage surfaces showed improved structure and cellularity for all treatments. PTJC involves multiple tissues and cell types, and thus a multitreatment approach will likely be needed to address all underlying causes: biological modulation of the inflammatory response combined with physical disruption of fibrotic tissue may show more efficacy than either treatment alone.

Differential effects and underlying mechanisms of voluntary, forced, and combined exercise on ameliorating Alzheimer's disease pathophenotypes.

Activation of the cGAS-STING pathway contributes to cancer-related fatigue in a murine model of head and neck cancer.

Co-administration of digoxin and trans-2-decenoic acid ethyl ester improves motor learning performance in mice.

ABSTRACTAn acute bout of high intensity exercise can transiently increase circulating extracellular vesicles (EVs) that possess beneficial molecular cargo. However, no studies to date have comprehensively evaluated plasma quantity, protein content, and function of EVs collected from blood after multiple bouts of endurance exercise. Here we demonstrate that 4 weeks of voluntary wheel running increases plasma EV quantity when collected immediately after the last bout of training in mice. These EVs (ExerVs) are enriched in oxidoreductases, including the antioxidant glutathione peroxidase 1 (GPX1). Repeated, systemic injections of ExerVs into sedentary recipient mice twice per week for 4 weeks did not alter mitochondrial content or function, fiber size, or fiber type, but increased capillary density and perfusion in skeletal muscle. ExerVs also stimulated tube formation and branch lengthening in vitro and improved the recovery of capillary content after a period of disuse in vivo. ExerVs isolated from GPX1−/− mice lacked the ability to stimulate vessel formation, whereas GPX1‐encapsulated liposomes robustly increased capillary growth, both in vitro and in vivo. The results from this study suggest that circulating ExerVs positively impact vascular structure and function in skeletal muscle in a manner that may be dependent on GPX1.

Maternal exercise may influence long-term cardiovascular health in offspring, yet its effects on intrinsic myocardial performance and mitochondrial metabolism remain incompletely defined. We investigated whether maternal voluntary wheel running before and during pregnancy is associated with cardiac adaptations in adult offspring. Female C57BL/6J mice were assigned to sedentary (Sed) or exercise (Ex) groups, with running initiated 3 weeks before mating and continued through gestation and lactation. Adult offspring (29-32 weeks) underwent high-fidelity pressure-volume (P-V) loop analysis at baseline and, in females, during β-adrenergic stimulation to assess systolic reserve. Cardiac mitochondria were evaluated by high-resolution respirometry together with measurements of reactive oxygen species emission. Maternal exercise did not alter maternal body weight before delivery or adult offspring body weight, whereas cardiac mass index was significantly lower in A-Ex offspring than in A-Sed offspring. Baseline hemodynamics were largely similar between maternal groups. In females, maternal exercise was associated with lower end-systolic elastance (Ees) at rest and a greater dobutamine-induced increase in Ees, consistent with enhanced load-independent systolic reserve. Mitochondrial analyses revealed substrate-dependent adaptations in females: maternal exercise was associated with lower pyruvate/malate-supported LEAK respiration, higher fatty acid-supported LEAK respiration, and reduced fatty acid coupling efficiency compared with sedentary offspring. ROS emission, sarcoplasmic reticulum Ca2+-handling proteins, fetal gene expression, and collagen-related transcript expression were unaffected. These findings suggest persistent functional and mitochondrial respiratory adaptations in adult offspring following maternal exercise, with the clearest adaptations observed in females.

To explore the role of polyamine metabolism in muscle-type-specific hypertrophy, we analyzed changes in the expression profiles of polyamine metabolic enzymes and key enzymes for muscle metabolism induced by voluntary wheel running exercise in different muscle types. Effect of the polyamine precursor, putrescine, which was reported to have potential to regulate muscle volume, was also tested. Polyamine synthetic enzymes were upregulated in hypertrophic soleus muscle whereas polyamine catabolic enzymes were upregulated in non-hypertrophic plantar muscle by exercise in correlation with increased mitochondria-related protein expression. The increased catabolic enzymes of polyamines in the plantar muscle were hypothesized to be possibly involved in restriction of hypertrophy in fast-type skeletal muscles correlating with increased aerobic metabolism. Putrescine administration minimally affected polyamine metabolism and muscle volume indicating that it did not effectively regulate muscle hypertrophy. Polyamine oxidase localized in the perinuclear and inter-myofibrillar region suggesting a correlation between aerobic metabolism and polyamine catabolism.

CD59 is known as a membrane-bound regulator of the complement system that prevents the formation of the membrane attack complex on host cells. Here we report the metabolic consequences of CD59a knockout (KO) in mice fed a high-fat diet (HFD). Mice lacking CD59a were protected from the development of insulin resistance, glucose intolerance, hyperinsulinemia, obesity, and fatty liver. Mutants fed an HFD had elevated adiponectin levels and reduced leptin levels in plasma. Data from metabolic cages suggested decreased appetite and an increase in voluntary wheel activity in mutants. Liver transcriptome analysis showed a marked decrease of inflammatory and fibrotic pathways in CD59a KO mice on an HFD, and plasma and liver metabolomics were remarkably similar, indicating close correspondence between systemic and hepatic metabolic profiles. In conclusion, we uncover a noncanonical role of CD59a in the development of diet-induced insulin resistance, hyperinsulinemia, glucose intolerance, and obesity.

ABSTRACTAlzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline. Although AD is primarily an age‐related brain pathology, increasing evidence indicates dysfunction in peripheral nerves and skeletal muscle may manifest early in the disease progression. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood. Sciatic nerves from 5xFAD and wild‐type (WT) mice were analyzed by tandem mass tag (TMT)‐labeled proteomics at 3, 4, and 7 months, identifying proteome remodeling coincides with functional declines at 4 months particularly in pathways linked to mitochondrial turnover, calcium handling, and inflammation. We hypothesized either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Separate cohorts, using 3‐month‐old 5xFAD mice and WT littermates, were given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil. We assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in vivo at 4 months. Both exercise and donepezil attenuated in vivo nerve‐stimulated muscle torque and CNAP dysfunction. Further, both exercise and donepezil attenuated the proteomic remodeling of the sciatic nerve through both shared and independent mechanisms that converged on mitochondria‐centric pathways. Our findings in the 5xFAD model of AD support the notion that early phenotypes of AD are evident in the periphery that may have implications for timing of interventions.

BACKGROUNDAlong with advancing age comes declines in physical, cognitive, and cardiovascular function. This diminished capacity may lead to decreased ability to perform activities of daily living, disability onset, and loss of independence. Exercise is a regenerative medicine therapy that can mitigate this loss of function. High intensity interval training (HIIT) is an aerobic exercise paradigm consisting of intense activity periods interspersed with bouts of active recovery. Previously we demonstrated that HIIT preserved physical function in adult, middle-aged, and older male mice. However, whether HIIT preserves physical, cognitive, and cardiovascular function, mitigates frailty, and improves brain and heart health in older adult female mice remains unknown.HYPOTHESISCognitive, physical, and cardiovascular function in older adult female C57BL/6 will be preserved in exercised mice (HIIT) versus sedentary control (SED).METHODSMice (HIIT and SED, both n=9, 24m at end) were tested pre/post-intervention for physical (rotarod, treadmill, grip meter, inverted cling, voluntary wheel running, activity monitor), cognitive (open field, novel object recognition, puzzle box, y-maze), and cardiovascular (blood pressure, echocardiogram) function, body composition, and whole body calorimetry. The mice underwent 14-weeks of HIIT training with progressive volume and intensity.RESULTSHIIT significantly (p<0.05) increased or preserved function in many tests including: aerobic capacity (+71% HIIT versus, vs, no change, NC, in SED), four limb strength/endurance (−67% SED vs -28% HIIT), forelimb strength (−16% SED vs NC HIIT), overall motor function (NC SED vs +39% HIIT), executive function (NC SED vs +73% HIIT), and exploratory behavior, which improved across multiple tests with HIIT while remaining unchanged in SED. HIIT also reduced both systolic blood pressure by 12% (−17 mmHg) and mean arterial pressure by -16 mmHg. In addition, HIIT significantly reduced cardiac fibrosis, increased muscle fiber type 2a percentage, reduced IL-1β expression in the hypothalamus, and mitigated frailty onset.CONCLUSIONHIIT significantly reduced age-related functional loss in all three domains assessed while preventing frailty onset in older adult females and improving markers of brain and heart health.

Cancer-related fatigue is one of the most reported issues following cancer and its treatment, affecting the quality of life of cancer patients and survivors. However, the effects of chemotherapy on motivational and decision-making processes related to fatigue remain unclear. This study aimed to examine the effects of the chemotherapeutic agent doxorubicin (DOX) on physical and cognitive effort-based decision-making using novel behavioural procedures in rats. Female Sprague-Dawley rats received DOX (2mg/kg, i.p.) or vehicle once weekly for four weeks. Voluntary wheel running was used to assess general physical activity. Physical effort-based decision-making was assessed with a T-maze concurrent choice paradigm, in which rats chose between climbing a 30-cm barrier for a high reward (HR) or entering a barrier-free arm for a low reward. Cognitive effort-based decision-making was assessed using a choice task involving lever pressing under differential reinforcement of low-rate schedules requiring different levels of response inhibition. DOX transiently reduced voluntary activity but did not impair either physical or cognitive effort expenditure. In the T-maze, DOX-treated rats showed greater perseveration than vehicle-treated rats by continuing to choose the HR arm even after reward reduction. In the cognitive effort task, DOX-treated rats similarly perseverated by continuing to choose the HR lever despite increased inhibition demands. These findings suggest that while DOX did not directly impair effort-based decision-making, it may disrupt executive function processes, particularly behavioural flexibility and working memory, which are critical for adapting behaviour to changing task contingencies and translating effort costs into goal-directed behaviour.

We investigated the prophylactic effects of exercise before and during cancer cachexia (CC) using a model designed to mimic endurance and resistance (i.e., concurrent) adaptations. Male and female Balb/c mice were randomly assigned to exercise or control groups whereby exercise groups were subjected to an 8-week voluntary progressive weighted wheel running (PoWeR) programme of habitual loading-mediated physical activity beginning at 8weeks of age. At 16weeks of age, mice were injected bilaterally with colon-26 adenocarcinoma (C26) cells or phosphate-buffered saline, and exercise training was maintained throughout disease progression. Twenty-five days post-tumour induction, we assessed whole-body and muscle phenotype, muscle protein synthesis, a priori targeted gene expression, and transcriptomic adaptations via RNA sequencing. PoWeR training preserved skeletal muscle mass across nearly all muscle groups and maintained tumour-free body and cardiac mass. Muscle mass adaptations related to running volume, and running distance relative to controls were not appreciably reduced by tumour status. Tumour burden was reduced after ∼11.5weeks of PoWeR compared to sedentary, but this was not explanatory for muscle adaptations. PoWeR induced a faster-to-slower muscle fibre type transition in the gastrocnemius and suppressed key protein turnover markers (Redd1, Murf1, Atrogin, Ubc, Gadd45a) as well as the mitophagy-related marker Bnip3 in tumour-bearing muscle; 24h muscle protein synthesis remained stable. PoWeR counteracted tumour-induced impairments in the muscle mitochondrial- and metabolic-related transcriptome. Collectively, physical activity prior to and during cancer preserves muscle mass, reduces tumour growth and mitigates molecular drivers of CC, underscoring its preventive and therapeutic potential as a lifestyle intervention. KEY POINTS: Cancer cachexia (CC) is a severe, multifactorial syndrome with limited effective therapies. Exercise training has emerged as a promising non-pharmacological approach to mitigate CC. Concurrent endurance and resistance training, initiated prior to and maintained during cancer, preserves skeletal muscle mass and reduces tumour burden in C26 colorectal tumour-bearing mice. Concurrent exercise training suppresses key mitochondrial- and metabolic-related molecular mediators of CC. Concurrent exercise training may serve as a preventive and therapeutic non-pharmacological strategy against CC.

This study aims to investigate the effects of voluntary exercise on liver levels of amyloid β (Aβ) and serum concentrations of LRP1, focusing on peripheral clearance in a rat Alzheimer's disease model. Forty male Wistar rats (aged 4-6 weeks) were randomly divided into four groups: Healthy control, Alzheimer's disease (Alz), control + exercise (Con-Ex) and Alzheimer's disease + exercise (Alz-Ex). Alzheimer's disease was induced by an intraventricular STZ injection and the disease was confirmed with the shuttle box test. Rats randomized to the exercise intervention were given continuous access to a running wheel of 12 weeks. At the end of the study memory (Morris Water Maze), serum LRP1 level and liver Aβ40 were measured. Data were analyzed by one-way ANOVA and Tukey's post hoc test. The results of the study indicate that compared to Alz voluntary exercise significantly improved Morris Water Maze performance (Alz: 153.2 ± 19.95; Alz-Ex:106.8 ± 18.89; p<0.001) and decreased liver concentration of Aβ40 (Alz: 40.06 ± 6.17; Alz-Ex: 25.12 ± 2.92; p<0.001) levels similar to non-exercising control animals. Serum concentrations of LRP1 were not impacted by exercise. These results suggest that voluntary wheel running may positively reduce hepatic concentrations of Aβ40 in Alzheimer's disease independent of changes in circulating LRP1. Further research is needed to better understand the role of exercise in assisting in clearing Aβ40 in this model.

It is well known that exercise training (TRN) and ischemic preconditioning (IPC) reduce cardiomyocyte (CM) death following ischemia and reperfusion (IR), but it is unknown if protection can be elicited by moderate exercise TRN or if the effects of TRN and IPC summate to generate greater protection than either protocol alone. To address these questions, we used wheel running, a moderate-intensity paradigm, to TRN male and female rats, and two IPC protocols. Hearts were studied ex vivo with regional ischemia (RI) produced by occluding the left anterior descending coronary artery for 30 min followed by 3 h reperfusion. IPC consisted of a 5-min period of global ischemia and either 5 (PC5) or 10 (PC10) min reperfusion before the initiation of index RI. We found that wheel running and PC10, but not PC5, reduced CM death compared with sedentary, with the TRN effect greater in males. TRN, but not IPC, showed functional protection by reducing the loss of left ventricular developed pressure. Surprisingly, the TRN and PC10 protection from cell death was not additive, suggesting that these modalities converge on the same pathway. We also showed that TRN significantly improved mitochondrial respiration and ΔΨm repolarization during oxidative phosphorylation after IR when compared with SED rats; the improved bioenergetics was associated with the increased prosurvival kinase, hexokinase II (HKII), translocation to mitochondria, which was mediated by increased total Akt and the phosphorylated Akt. We conclude that TRN-induced cardioprotection is mediated, in part, by preservation of mitochondrial bioenergetics likely mediated via the Akt-pAkt-HKII signaling pathway.NEW & NOTEWORTHY Our study produced the novel findings that wheel running in rats, a form of moderate-intensity continuous training (MICT), can provide protection against IR injury as evidenced by a reduction in cardiomyocyte death following 3 h reperfusion and that the protection generated by MICT and IPC is not additive. Importantly, we demonstrate for the first time that MICT-induced cardioprotection is associated with preservations of mitochondrial bioenergetics likely by the Akt-pAkt-HKII signaling pathway.

Parkinson's disease (PD) is a neurodegenerative disorder marked by loss of substantia nigra dopaminergic neurons. Epidemiological evidence indicates that lifelong physical activity reduces both PD incidence and slows disease progression. Here, we examine how voluntary exercise induces long-lasting neuroprotection of the corticostriatal function in a murine model of α-synuclein-driven nigrostriatal pathology. In preformed fibril (PFF)-injected mice, long-lasting voluntary wheel running prevents degeneration of nigrostriatal dopaminergic terminals and improves motor performances. Intensive exercise normalizes spontaneous glutamatergic transmission and preserves corticostriatal long-term potentiation (LTP) in striatal spiny projection neurons. Exercise-induced LTP is dependent on activation of dopamine (DA) DA1, GluN2B-expressing NMDA and CB1 endocannabinoid (eCB) receptors. Pharmacological modulation of exercise-induced plasticity shows that, while in physiological conditions eCBs regulate synaptic depotentiation, persistence of LTP in active α-syn mice occurs independently of the eCB system, highlighting a critical interaction between DA and eCBs in long-term synaptic regulation. These findings identify voluntary exercise as a robust neuroprotective intervention with therapeutic relevance for early PD.

Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice.

A metabolic basis for motor deficits in mice lacking BCKDK.

Effect of alternate-day fasting combined with and without voluntary running exercise on body composition and energy metabolism in young adult, normal-weight mice.