Voluntary Wheel Running Research Articles

A convolutional neural network to characterize mouse hindlimb foot strikes during voluntary wheel running.

Voluntary wheel running (VWR) is widely used to study how exercise impacts a variety of physiologies and pathologies in rodents. The primary activity readout of VWR is aggregated wheel turns over a given time interval (most often, days). Given the typical running frequency of mice (∼4Hz) and the intermittency of voluntary running, aggregate wheel turn counts, therefore, provide minimal insight into the heterogeneity of voluntary activity. To overcome this limitation, we developed a six-layer convolutional neural network (CNN) to determine the hindlimb foot strike frequency of mice exposed to VWR. Aged female C57BL/6 mice (22months, n = 6) were first exposed to wireless angled running wheels for 2h/d, 5days/wk for 3weeks with all VWR activities recorded at 30 frames/s. To validate the CNN, we manually classified foot strikes within 4800 1-s videos (800 randomly chosen for each mouse) and converted those values to frequency. Upon iterative optimization of model architecture and training on a subset of classified videos (4400), the CNN model achieved an overall training set accuracy of 94%. Once trained, the CNN was validated on the remaining 400 videos (accuracy: 81%). We then applied transfer learning to the CNN to predict the foot strike frequency of young adult female C57BL6 mice (4months, n = 6) whose activity and gait differed from old mice during VWR (accuracy: 68%). In summary, we have developed a novel quantitative tool that non-invasively characterizes VWR activity at a much greater resolution than was previously accessible. This enhanced resolution holds potential to overcome a primary barrier to relating intermittent and heterogeneous VWR activity to induced physiological responses.

Effects of high-resistance wheel running on hallmarks of endurance and resistance training adaptations in mice.

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, and cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve the mechanistic study of specific exercise training adaptations, standardized, physiological, and well-characterized training interventions are required. Therefore, we performed a comprehensive interrogation of systemic changes and muscle-specific cellular and molecular adaptations to voluntary low-resistance wheel running (Run) and progressive high-resistance wheel running (RR) in young male mice. Following 10 weeks of training, both groups showed similar improvements in body composition and peak oxygen uptake (V̇O2peak ), as well as elevated mitochondrial proteins and capillarization markers in the M. plantaris. Run mice clearly outperformed RR mice in a forced treadmill running capacity test, while RR mice displayed increased grip strength as well as superior mass gains in the M. soleus, associated with distinct proteomic changes specifying the two paradigms. Thus, even though both training modalities induce overlapping adaptations, Run interventions preferably improve submaximal running performance, while progressive RR is a valid model to study training-induced gains in grip strength and plantar flexor hypertrophy.

Voluntary physical activity modulates self-selection of a high-caloric choice diet in male Wistar rats

Physical exercise training has been positioned as a behavioral strategy to prevent or alleviate obesity via promotion of energy expenditure as well as modulation of energy intake resulting from changes in dietary preference. Brain adaptations underlying the latter process are incompletely understood. Voluntary wheel running (VWR) is a self-reinforcing rodent paradigm that mimics aspects of human physical exercise training. Behavioral and mechanistic insight from such fundamental studies can help optimize therapies that improve body weight and metabolic health based on physical exercise training in humans.To assess the effects of VWR on dietary self-selection, male Wistar rats were given access to a two-component “no-choice” control diet (CD; consisting of prefabricated nutritionally complete pellets and a bottle with tap water) or a four-component free-choice high-fat high-sucrose diet (fc-HFHSD; consisting of a container with prefabricated nutritionally complete pellets, a dish with beef tallow, a bottle with tap water, and a bottle with 30% sucrose solution). Metabolic parameters and baseline dietary self-selection behavior during sedentary (SED) housing were measured for 21 days, after which half of the animals were allowed to run on a vertical running wheel (VWR) for another 30 days. This resulted in four experimental groups (SEDCD, SEDfc-HFHSD, VWRCD, and VWRfc-HFHSD). Gene expression of opioid and dopamine neurotransmission components, which are associated with dietary self-selection, was assessed in the lateral hypothalamus (LH) and nucleus accumbens (NAc), two brain regions involved in reward-related behavior, following 51 and 30 days of diet consumption and VWR, respectively.Compared to CD controls, consumption of fc-HFHSD before and during VWR did not alter total running distances. VWR and fc-HFHSD had opposite effects on body weight gain and terminal fat mass. VWR transiently lowered caloric intake and increased and decreased terminal adrenal and thymus mass, respectively, independent of diet. VWR during fc-HFHSD consumption consistently increased CD self-selection, had an acute negative effect on fat self-selection, and a delayed negative effect on sucrose solution self-selection compared to SED controls. Gene expression of opioid and dopamine neurotransmission components in LH and NAc were unaltered by fc-HFHSD or VWR. We conclude that VWR modulates fc-HFHSD component self-selection in a time-dependent manner in male Wistar rats.

Wheel Running Exacerbates Joint Damage after Meniscal Injury in Mice, but Does Not Alter Gait or Physical Activity Levels.

Exercise and physical activity are recommended to reduce pain and improve joint function in patients with knee osteoarthritis (OA). However, exercise has dose effects, with excessive exercise accelerating OA development and sedentary behaviors also promoting OA development. Prior work evaluating exercise in preclinical models has typically used prescribed exercise regimens; however, in-cage voluntary wheel running creates opportunities to evaluate how OA progression affects self-selected physical activity levels. This study aimed to evaluate how voluntary wheel running after a surgically induced meniscal injury affects gait characteristics and joint remodeling in C57Bl/6 mice. We hypothesize that injured mice will reduce physical activity levels as OA develops after meniscal injury and will engage in wheel running to a lesser extent than the uninjured animals. Seventy-two C57Bl/6 mice were divided into experimental groups based on sex, lifestyle (physically active vs sedentary), and surgery (meniscal injury or sham control). Voluntary wheel running data were continuously collected throughout the study, and gait data were collected at 3, 7, 11, and 15 wk after surgery. At end point, joints were processed for histology to assess cartilage damage. After meniscal injury, physically active mice showed more severe joint damage relative to sedentary mice. Nevertheless, injured mice engaged in voluntary wheel running at the same rates and distances as mice with sham surgery. In addition, physically active mice and sedentary mice both developed a limp as meniscal injury progressed, yet exercise did not further exacerbate gait changes in the physically active mice, despite worsened joint damage. Taken together, these data indicate a discordance between structural joint damage and joint function. Although wheel running after meniscal injury did worsen OA-related joint damage, physical activity did not necessarily inhibit or worsen OA-related joint dysfunction or pain in mice.

Voluntary wheel running and lithium supplementation promotes fatigue resistance, fat oxidation, and improves insulin tolerance in D2 mdx mice

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle wasting and premature death. Many DMD patients will also exhibit signs of metabolic dysfunction such as insulin resistance that predisposes them to type 2 diabetes and worsened cardiovascular disease. Most treatments for DMD aim to lower muscle inflammation and improve strength, however, none have addressed the complication of insulin resistance. The current standard of treatment is corticosteroids, which prolongs ambulation, however, chronic use increases susceptibility to obesity, insulin resistance, and type 2 diabetes. It is well-established that regular aerobic exercise enhances insulin sensitivity. Further, we have recently found that inhibiting glycogen synthase kinase 3 with lithium (Li), a known insulin mimetic, improves force production and fatigue resistance in wildtype (WT) mice. Here, we tested whether voluntary wheel running (VWR) and Li supplementation, together, could improve whole-body fatigue, metabolism, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. METHODS: 5-week old male D2 WT and mdx mice were separated into four groups: WT, mdx sedentary (SED), mdx VWR, and mdx Li+VWR (n=11/group). The mdx VWR and mdx Li+VWR mice had unlimited access to a cagewheel, and mdx Li+VWR mice were given a low dose of Li (50 mg/kg/day) via their drinking water throughout the study. A treadmill time-to-fatigue test was performed to assess whole-body fatigue. Mice were housed for 48-hours in metabolic cages to measure energy expenditure. Glucose handling was measured using glucose and insulin tolerance tests. RESULTS: As expected, WT mice had ~2-fold greater total cage activity compared to all mdx groups. When examining cagewheel distance, we found that mdx Li+VWR mice ran half the total distance in kilometres than mdx VWR mice (39.1 ± 9.6 km vs. 74.8 ± 13.6 km). Despite this, VWR with and without Li improved whole-body fatigue as only mdx SED mice (22.8 ± 0.9 min) had a shorter time to exhaustion than WT mice (32.6 ± 0.9 min). All mdx groups had higher energy expenditure than WT mice, suggestive of a hypermetabolic phenotype. When examining the respiratory exchange ratio (RER) among mdx mice, mdxLi+VWR (0.87) mice had a lower RER than mdx SED mice (0.91), indicative of enhanced fat oxidation. Glucose tolerance was equally impaired among mdx groups compared to WT mice. However, insulin tolerance was notably improved in mdx VWR and mdx Li+VWR mice, with a greater improvement observed in the mdx Li+VWR mice. CONCLUSION: Despite running less than mdx VWR mice, mdx Li+VWR mice had enhanced fatigue resistance, fat utilization, and insulin sensitivity, suggesting Li may be a viable treatment to improve muscle and metabolic function in mdx mice. CIHR CRC (Tier II) to VAF This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Voluntary wheel running and lithium supplementation improves muscle force production without altering SERCA function in the D2 mdx mouse

Background: Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease that, with no cure, leads to early mortality (30-40 years of age). Previous studies have shown that voluntary wheel running can mitigate disease pathology and improve muscle contractility in the preclinical mdx mouse model. We have shown that treating wild-type (WT) mice with a low dose of lithium, a natural inhibitor of glycogen synthase kinase 3, enhanced soleus (SOL) and extensor digitorum longus (EDL) muscle contractility. Our objectives were to test our hypothesis of whether combining VWR with low dose lithium supplementation could provide further benefits to muscle contractility in DBA/2J mdx mice – a model that displays far worse disease severity compared with the traditional C57BL/10 mdx mouse. We also examined if this combined intervention could improve muscle calcium regulation in muscle by assessing sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) function as we have recently shown that SERCA function is drastically impaired in D2 mdx mice, which could also contribute to deficits in muscle force production. Methods: Young (5-6 week old) male D2 WT and mdx mice were ordered from Jackson Laboratory. D2 mdx mice were assigned into each of the following conditions: sedentary ( mdxSED), voluntary wheel running ( mdxVWR), or VWR+lithium chloride ( mdxVWR+Li). The VWR groups were given access to a cagewheel for a total of 6 weeks, and the mdxVWR+Li group were provided a low dose of LiCl (50 mg/kg/day) via drinking water for the entire duration of the study. After 6 weeks, all mice were euthanized and the SOL and EDL muscles were subjected to force-frequency curve analysis (1-160 Hz). SERCA function was assessed by performing SERCA activity assays and a Ca 2+ uptake assay. Results: In the SOL, the combined effect of lithium and VWR improved specific force production to near WT levels across submaximal and maximal frequencies. Specific force production in the mdxVWR+Li group was significantly greater compared to the mdxSED group at all stimulation frequencies. Rate of SOL force development was significantly lower in all mdx groups compared to WT. However, rate of relaxation was only significantly reduced (vs. WT) within the mdxSED group, suggesting that VWR and VWR+Li improved relaxation. This could not be explained by any changes in SERCA function. In the EDL, specific force was significantly (p<0.001) reduced across mdx groups compared to WT; however, of all mdx groups, the mdxVWR+Li produced the most force and was significantly different compared to mdxVWR at 80 and 160 Hz. Rates of force development and relaxation were all slower in all mdx groups compared to WT, and there were no differences in SERCA activity. Conclusions: Combining lithium supplementation with VWR improved SOL and EDL force production in the D2 mdx mouse without any changes to SERCA function. V.A.F is a Tier 2 Canada Research Chair in Muscle Plasticity and Tissue-Remodelling. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Behavioral and neural network characterizations of the reinforcement of voluntary physical activity in heterogenous mice

Maintaining healthy and consistent levels of physical activity (PA) is a cost-effective means of reducing the onset of >40-chronic diseases; however, these benefits go largely unrealized by the ~97% of adult Americans who fail to meet activity guidelines. Our prior work suggests that acute activity engages aversion-related brain regions, which may act as a barrier to PA adherence. Chronic PA is reinforcing and creates neural remodeling a across a network of brain regions belonging to the mesocorticolimbic system - comprising of stress and aversion-related brain regions [such as the basolateral amygdala (BLA)] and important reinforcement brain regions [i.e., the ventral tegmental area (VTA)]. A primary focus of this study is to determine how neural inputs to the nucleus accumbens (NAc) -the central point of convergence for this system– are engaged during acute and chronic PA. Objectives: Here we tested whether sex differences in the reinforcing value of wheel-running exist in a genetically diverse population of mice, the Heterogeneous Stock/Northport (HS/Npt). Moreover, we sought to identify the neural circuits engaged during acute and chronic voluntary wheel-running in these mice. Hypothesis: Given established findings that female rodents run more than males, we hypothesized that female HS/Npt mice would find wheel-running less aversive than males. We further hypothesized that 1-week of voluntary wheel-running would increase cFos expression (compared to mice with 1-week of wheel-lock) in brain regions associated with stress and aversion, whereas 4-weeks of wheel-running would increase neural engagement in brain regions associated with reinforcement, including the NAc, insular cortex, VTA and the medial preoptic area (a sexually dimorphic brain region critical for the estrogenic control of wheel-running in female rodents). Methods: As a proxy for their hedonic state, mice were provided a two-bottle choice saccharin preference test following acute or chronic PA. To better define the mesocorticolimbic system, we used an established retrograde tracer (rAAV-retro) to label the neural inputs to the NAc, which helped to identify important brain region involvement at two distinct stages of PA reinforcement. Results: There were no differences in running distance between female and male mice at 1- or 4-weeks and no differences in saccharin preference at 1-week. In contrast, male HS/Npt showed lower saccharin preference compared to females at 4-weeks of voluntary wheel running, suggesting a potential sex difference in the reinforcement value of chronic PA. Whole brain cFOS imaging is currently underway. Conclusions: It appears that chronic voluntary activity may confer lower hedonic states in male mice. Moreover, an improved understanding of how neural circuits across the mesocorticolimbic system are engaged during crtical stages of PA (in males and females) may prove important for determining neural and behavioral barriers to exercise adherence in humans. American College of Sports Medicine This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Maternal exercise improves markers of metabolic signaling and reduces inflammation in brown adipose tissue of offspring

Maternal obesity impacts approximately one-third of pregnant people and impacts offspring through the transmission of obesogenic and diabetic traits. Pregnant patients often spend considerable time sedentary, which has been associated with harmful cardiometabolic changes. Our recent data show that compared with sedentary conditions, voluntary exercise during pregnancy in mice shifts adipose distribution of offspring away from energy storing white adipose tissue towards energy burning brown adipose tissue (BAT), which could improve energy metabolism over the lifespan. The objective of this study was to test the hypothesis that voluntary exercise in pregnant mice improves metabolic signaling pathways and reduces markers of inflammation in BAT from offspring. To test this, female C57BL/6J mice were placed on control diet and allocated to sedentary versus voluntary running wheel exercise cages. Voluntary wheel running was allowed for two weeks prior to breeding and throughout weaning. When offspring were 16 weeks of age, they were euthanized for collection of BAT. The study groups were male sedentary (n=9), female sedentary (n=11), male exercise (n=12), female exercise (n=8). Quantitative real-time polymerase chain reaction was used to measure mRNA of fibroblast-growth factor receptors (β-klotho, Fgfr1, Fgfr2) and inflammation markers (IL10, IL1β, TNFα) in BAT. Outcomes were analyzed by two-way ANOVA to assess effects of exercise, sex, and their interaction. Offspring from exercised mothers had a significant decrease in mRNA of IL1β (1.4±0.4 male sedentary vs. 0.4±0.1 male exercise vs. 1.1±0.2 female sedentary vs. 0.8 ±0.2 female exercise; PSex=0.668, PEX=0.006, PInt=0.098) and TNFα (0.9±0.1 male sedentary vs. 0.5±0.1 male exercise vs. 1.3±0.3 female sedentary vs. 0.6 ±0.1 female exercise; PSex=0.126, PEX=0.007, PInt=0.562) and an increase in Fgfr2 (1.1±0.2 male sedentary vs. 1.7±0.3 male exercise vs. 1.3±0.3 female sedentary vs. 3.8 ±1.2 female exercise; PSex=0.063, PEX=0.011, PInt=0.096) in BAT, which was largely independent of sex. There was no significant main effect of either sex or exercise on IL10, Fgfr1, or β-klotho mRNA in BAT. These data suggest that maternal exercise is associated with decreased inflammation and increased protective metabolic signaling in BAT. This could impact energy metabolism given increasing evidence for advantageous metabolic adaptations with increased BAT health and signaling. Additional studies are needed to further understand the impact of maternal exercise on adipose health, energy metabolism, and cardiovascular outcomes in offspring over the lifespan. American Heart Association Undergraduate Summer Fellowship, Department of Obstetrics and Gynecology at Penn State Milton S Hershey Medical Center, and Dani Peress MD Memorial Fund from the Society of Maternal Fetal Medicine This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lifelong voluntary aerobic exercise-mediated preservation of physical function is related to changes in the plasma metabolome in aged mice

Declines in physical function with aging (i.e., grip strength, endurance, and coordination) are strongly linked to age-related diseases, and the plasma metabolome can predict the progression of healthy aging. A single bout of aerobic exercise induces changes in plasma metabolites that are implicated in healthy aging and lifespan (e.g., tRNA biosynthesis is required for protein synthesis; arginine biosynthesis contributes to nitric oxide production and skeletal muscle function; TCA cycle metabolites aid in cellular energy production). Moreover, lifelong voluntary aerobic exercise (VAE) preserves physical function with aging, but its relation to the plasma metabolome is unknown. Hypothesis: Lifelong VAE-mediated preservation of physical function is related to changes in the plasma metabolome. Design: We performed a secondary analysis of data from a lifelong study in male C57BL/6 mice, in which mice that engaged in voluntary wheel running (model of VAE; initiated at 3 mo) were compared to sedentary age-matched controls (SED) (n=8-9/group). Grip strength, endurance, and coordination were assessed at 6 and 18 mo. The plasma metabolome was measured at 19 mo by mass spectrometry. Group differences in metabolites were identified using independent t-tests (p<0.05) following a Shapiro-Wilk test of normality. Then, KEGG pathway analyses (Metaboanalyst) were used to identify metabolic pathways changed with VAE (p<0.05; false discovery rate<0.20). Finally, simple linear regressions were used to assess the relation between the magnitude of change in grip strength, endurance, and coordination from 6 to 18 mo and plasma metabolite concentrations (all p<0.05). Results: At 19 mo, VAE mice ran 3.2±0.1 km/day (mean±SE). Physical function was preserved from 6 to 18 mo (% decline) with VAE vs SED: grip strength, 0.4±1.7% vs 12±4.0% (p<0.05); endurance, 1±15% vs 61±5% (p<0.05); coordination, 10±4% vs 73±10% (p<0.05). Group-related differences in plasma metabolites were identified at 19 mo: 23 single metabolites (p<0.05) and 7 metabolic pathways. The top altered metabolic pathways are implicated in healthy aging (e.g., tRNA and arginine biosynthesis) and exercise metabolism (e.g., TCA cycle). Metabolomic differences in the VAE mice were associated with preservation of physical function: spermidine and DHA omega-3 fatty acid correlated with the change in grip strength, spermidine and L-ornithine correlated with the change in endurance, and 9 metabolites (e.g., citrate and spermidine) correlated with the change in coordination. Conclusions: We show associations between the preservation of physical function with lifelong VAE and plasma metabolite abundance. Plasma metabolomic differences in aged mice following lifelong VAE are consistent with observations of corresponding changes in response to acute exercise in young endurance trained adults. Changes in the plasma metabolome reflect preserved physical function with lifelong VAE. NIH T32 DK007135, R01 HL107120, K99 HL159241 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex-specific effects of voluntary wheel running on behavior and the gut microbiota-immune-brain axis in mice

Physical exercise has been positioned as a promising strategy to prevent and/or alleviate anxiety and depression, but the biological processes associated with its effects on mental health have yet to be entirely determined. Although the prevalence of depression and anxiety in women is about twice that of men, very few studies have examined whether physical exercise could affect mental health differently according to sex. This study examined, in singly-housed mice, the sex-specific effects of voluntary exercise on depressive- and anxiety-like behaviors as well as on different markers along the gut microbiota-immune-brain axis. Male and female C57BL/6N mice had voluntary access to running wheels in their home-cages for 24 days or were left undisturbed in identical home-cages without running wheels. Behaviors were then examined in the open field, splash, elevated plus maze, and tail suspension tests. Gene expression of pro-inflammatory cytokines, microglia activation-related genes, and tight junction proteins was determined in the jejunum and the hippocampus, while microbiota composition and predicted function were verified in cecum contents. Voluntary exercise reduced anxiety-like behaviors and altered grooming patterns in males exclusively. Although the exercise intervention resulted in changes to brain inflammatory activity and to cecal microbiota composition and inferred function in both sexes, reductions in the jejunal expression of pro-inflammatory markers were observed in females only. These findings support the view that voluntary exercise, even when performed during a short period, is beneficial for mental and intestinal health and that its sex-specific effects on behavior could be, at least in part, related to some components of the gut microbiota-immune-brain axis.

Cisplatin decreases voluntary wheel-running activity but does not impair food-motivated behavior in mice

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less energy but also procures energy in the form of food. For this purpose, mice were either trained to run in a wheel or to work for food in various schedules of food reinforcement before being treated with cisplatin. The experiments were carried out only in male mice as we had already reported that sex differences in cisplatin-induced neurotoxicities are minimal. Cisplatin was administered daily for one cycle of five days, or two cycles separated by a five-day rest. As observed in previous experiments, cisplatin drastically reduced voluntary wheel running. In contrast, when cisplatin was administered to food-restricted mice trained to work for a food reward in a progressive ratio schedule or in a fixed-interval schedule, it tended to increase the number of responses emitted to obtain the food rewards. This increase was not associated with any change in the temporal distribution of responses during the interval between two reinforcements in mice submitted to the fixed interval schedule of food reinforcement. When cisplatin was administered to food-restricted mice trained in an effort-based decision-making task in which they had to choose between working for a grain pellet with little effort and working for a preferred chocolate pellet with more effort, it decreased the total number of responses emitted to obtain food rewards. However, this effect was much less marked than the decrease in wheel running induced by cisplatin. The decrease in the effort invested in the procurement of food rewards was not associated with any change in the relative distribution of effort between low reward and high reward during the time course of the test session. These findings show that cisplatin decreases energy-consuming activities but not energy-procuring activities unless they require a choice between options differing in their cost-benefit ratio. Furthermore, they indicate that the physical dimension of fatigue is more likely to develop in cisplatin-treated individuals than the motivational dimension of fatigue.

Chronic voluntary wheel running exercise ameliorates metabolic dysfunction via PGC-1α expression independently of FNDC5/irisin pathway in high fat diet-induced obese mice

Exercise is an effective intervention to ameliorate metabolic diseases including obesity and insulin resistance, but the mechanisms involved in the metabolic amelioration have not yet been fully elucidated. This study aimed to determine whether AMPK–SIRT1–PGC-1α–FNDC5/Irisin-UCP1 expression is activated and whether metabolic dysfunction is ameliorated by chronic voluntary wheel running (VWR) in high-fat diet (HFD) induced obese mice. C57BL6J mice were randomly assigned into three groups at the age of 7 weeks for 10 weeks: normal chow diet (CON) group, HFD group, and HFD + VWR group. Chronic VWR ameliorates metabolic parameters and leads to increases in the expression of PGC-1α in the gastrocnemius muscle in HFD-induced obese mice. In contrast, the expression of AMPKα, SIRT1, and FNDC5, or circulating irisin levels did not lead to alteration. Improvement of metabolic health was partly mediated via PGC-1α expression by chronic VWR, but not FNDC5/Irisin pathway in HFD-induced obese mice.

Voluntary wheel running ameliorates abnormalities in social behavior induced by social isolation: Involvement of neural and neurochemical responses

Social isolation (SI) can lead to devastating behavioral effects. Increasing evidence has demonstrated that physical activity can improve sociability and brain functions, but whether voluntary exercise can ameliorate SI-induced abnormalities in social behavior and its underlying neuronal mechanisms remains unknown. The present study found that SI during adulthood increased aggression in the resident-intruder test and motivation for social exploration in the three-chamber test. Voluntary wheel running (VWR) could reverse the alterations in social behavior induced by SI in male mice. In addition, SI increased the number of c-Fos-immunoreactive neurons and c-Fos/AVP-labeled neurons in the PVN, reduced c-Fos/TPH2-labeled neurons in the DRN. These alterations could be reversed by VWR. Together, our results reveal that voluntary exercise could ameliorate SI-induced negative effects on social behavior, possibly via alterations of neuronal activation in the brain. This finding provides a potential therapy and targets to prevent or treat the psychological diseases associated with abnormalities in social behaviors.

Exercise modifies fatty acid perception and metabolism.

Obesity is a major public health issue, which is associated with several chronic diseases. In rodents, voluntary wheel running (VWR) is a type of exercise that influences ingestive behavior. This study aims to investigate the possible function of VWR activity in the perception of fat taste and if it mitigates the immediate effects of fatty acid (FA) ingestion METHODS: Male C57BL/6 mice were arbitrarily assigned to either a sedentary (SED) lifestyle or free access to a running wheel after 5 weeks of dietary regimen. Later these mice groups were used in the investigations on fat preference, metabolic tolerance, and electrophysiology. Diet-induced alterations in CD36 and GPR120 expression that are related to fat perception and the capacitative calcium signaling caused by FA in taste bud cells (TBCs) were also examined. In obese groups, VWR temporarily reduced body weight, demonstrated improvement in preference scores for FA, and recovered from a deterioration in glucose homeostasis. In CD36-positive TBCs, electrophysiological investigations showed alterations in [Ca2+ ]i caused by FA. Further, in the TBCs of circumvallate papillae (CVP), there are differences in the expression of the genes CD36 and GPR120 between the active and SED controls. Obese mice also show lower incentive salience for long-chain fatty acids (LCFA) and adapted to the reward system of VWR which may lead to improved incentive salience accredited to wheel running CONCLUSION: In conclusion, this study provides the first evidence that VWR causes orosensory adaptations to fat and appears to alter taste preference for LCFAs.

Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice.

Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: -9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: -29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

Sex-Dependent Effects Of Voluntary Wheel Running On Hindpaw Sensitivity And Bilateral Hippocampal Methylation In Mice Exposed To Early Life Stress

Sex-Dependent Effects Of Voluntary Wheel Running On Hindpaw Sensitivity And Bilateral Hippocampal Methylation In Mice Exposed To Early Life Stress

Voluntary Wheel Running Improves Hippocampal Integrity, Cognitive Performance, And Urogenital Hypersensitivity In Adult Mice Exposed To Neonatal Maternal Separation

Voluntary Wheel Running Improves Hippocampal Integrity, Cognitive Performance, And Urogenital Hypersensitivity In Adult Mice Exposed To Neonatal Maternal Separation

Voluntary Exercise to Reduce Anxiety Behaviour in Traumatic Brain Injury Shown to Alleviate Inflammatory Brain Response in Mice

Traumatic brain injury is a leading cause of neuroinflammation and anxiety disorders in young adults. Immune-targeted therapies have garnered attention for the amelioration of TBI-induced anxiety. A previous study has indicated that voluntary exercise intervention following TBI could reduce neuroinflammation. It is essential to determine the effects of voluntary exercise after TBI on anxiety via inhibiting neuroinflammatory response. Mice were randomly divided into four groups (sham, TBI, sham + voluntary wheel running (VWR), and TBI + VWR). One-week VWR was carried out on the 2nd day after trauma. The neurofunction of TBI mice was assessed. Following VWR, anxiety behavior was evaluated, and neuroinflammatory responses in the perilesional cortex were investigated. Results showed that after one week of VWR, neurofunctional recovery was enhanced, while the anxiety behavior of TBI mice was significantly alleviated. The level of pro-inflammatory factors decreased, and the level of anti-inflammatory factors elevated. Activation of nucleotide oligomerization domain-like thermal receptor protein domain associated protein 3 (NLRP3) inflammasome was inhibited significantly. All these alterations were consistent with reduced microglial activation at the perilesional site and positively correlated with the amelioration of anxiety behavior. This suggested that timely rehabilitative exercise could be a useful therapeutic strategy for anxiety resulting from TBI by targeting neuroinflammation.

Effect of voluntary wheel running on autophagy status in lung tissue of high-fat diet-fed rats

Here, we aimed to explore the therapeutic effect of voluntary wheel running (VWR) in high-fat diet-fed rats on pulmonary tissue injury via the modulation of autophagic response. Thirty-two rats were allocated into four groups; normal diet (Control); VWR; high-fat-diet (HFD), and HFD + VWR. After three months, pathological effect of HFD on pulmonary tissue was investigated. The levels of tumour necrosis factor (TNF)-α were detected in the bronchoalveolar lavage fluid (BALF). We monitored the expression of interleukin (IL)-6 and autophagy-related genes in lung tissues. H&amp;E staining showed pathological changes in HFD group coincided with the increase of TNF-α levels in the bronchoalveolar fluid compared to the normal rats. Our results showed the up-regulation of IL-6, becline-1, LC3 and P62 in the HFD group compared to the Control group. VWR inhibited HFD-induced changes and could decrease HFD-induced changes via the regulation of autophagy status.

Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases.

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations. Methods: Female C57Bl/6J mice at 6weeks old were given free access to open voluntary running wheels for a period of 28days and then subjected to 5days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls. Results: Following 5days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina. Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype.