Regular exercise induces adaptations in skeletal muscle and other organ systems to improve physical performance and overall health. Exercise results in phosphorylation of 5' AMP-activated protein kinase (AMPK) at threonine 172 (T172) of the α2 subunit; however, the role of this activation in cellular and functional adaptations has not been elucidated. To this end, we subjected non-activatable Ampkα2(T172A) knock-in (KI) adult mice and wild-type (WT) littermates to 4 weeks of voluntary wheel running (VWR). Exercise training led to significant improvements in endurance capacity, maximal oxygen consumption ( V ˙ O 2 m a x ), and glucose tolerance, as well as skeletal muscle IIb-to-IIa fiber type shift in both WT and KI mice. Contrastingly, VWR resulted in increased mitochondrial OxPhos protein expression, mitochondrial volume density, and capillary density in skeletal muscle of WT but not KI mice. Exercise-induced improvements of mitochondrial respiration and conductance revealed by high-resolution respirometry of isolated mitochondria were blunted in KI mice. Therefore, for the first time, we reveal that AMPKα2 T172 activation is required for exercise training-induced mitochondrial biogenesis, improvement of mitochondrial respiratory function, and angiogenesis in skeletal muscle, but that these adaptations are not solely responsible for improved V ˙ O 2 m a x and exercise endurance capacity.

Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4 weeks of chronic treadmill running (5 days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1 h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1 h after acute exercise and 48 h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1 h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I + II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health. KEY POINTS: Decades of literature demonstrate endurance exercise to be neuroprotective. Whether neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. This study provides the first set of data that suggest hepatic ketogenesis is required to maintain cognition, synaptic plasticity and mitochondrial function. These data indicate endurance exercise can protect against cognitive decline caused by compromised hepatic ketogenesis. These results establish a mechanistic link between liver and brain function, prompting further investigation of how hepatic metabolism influences brain health.

How loss- or gain-of-function for a gene in skeletal muscle induces muscle phenotypes is an important topic. Two important underlying rationales are: (a) understanding the fundamentals of gene regulations in the skeletal muscle and (b) how they influence physiological and metabolic functions. The knowledge of gene functions in the skeletal muscle is crucial to target the selection of interventions that will promote muscle health, prevent muscle loss, and treat muscle diseases. This chapter briefly introduces current techniques, such as the Cre-LoxP system, and its application with muscle-specific gene promoters. These advances in studying skeletal muscle-specific gene manipulations in animal models consequently broadened our views of muscle phenotypes related to gene regulations. We then summarize some current findings in gene manipulations regarding muscle mass, fiber-type shifting, metabolism, muscle diseases, and exercise performance. Lastly, we discuss the precautions and future directions from the current knowledge. We anticipate that by using numerous examples in this chapter, readers could understand the concepts of genetic engineering contributing to altered skeletal muscle phenotype.

Exercise supports healthy aging in the brain leading to adaptations that slow cognitive decline, including increasing neurogenesis in the hippocampus and promoting the maintenance of mitochondrial function. Evidence demonstrates that exercise stimulates the release of factors, exerkines, that modulate systemic benefits. Extracellular vesicles (EVs) facilitate inter-organ crosstalk in response to exercise by disseminating exerkines. The liver, crucial to maintaining systemic metabolic homeostasis, undergoes substantial changes with exercise and is central to exercise induced adaptations that promote metabolic health. Taken together, these findings point to exercise induced liver derived EVs as a critical area of study in potentially mediating the benefit of exercise to brain health. Male and female 6-month old Fisher (F344) rats were randomized to sedentary or acute exercise conditions (30-minute treadmill running at 70-80% VO 2 max). Immediately after exercise, the common hepatic and portal veins were cannulated for blood sampling in anesthetized rats. EVs were isolated via serial ultracentrifugation and underwent global, untargeted proteomic analysis (n=4/5). Rat primary cortical neurons were cultured from isolated embryonic cortices and treated with pooled sedentary or exercised, male or female, common hepatic vein EVs for 4 hours at a concentration of 2.5ug/mL (n=3). Serum from which the EV populations were isolated was used as a control. Basal mitochondrial respiration was measured using a Seahorse XF. In females, we identified 119 significantly differentially expressed proteins (DEPs) in common hepatic vein EVs between exercise and sedentary conditions, 13 of which were only identified with exercise. While in males, we identified 120 DEPs, 7 of which were unique to exercise. In rat primary cortical neurons male derived hepatic EVs promoted increased basal mitochondrial respiration, predominantly driven by exercise (main effect of EVs, p<0.05), while exercise promoted increased basal mitochondrial respiration, largely driven by hepatic EVs, in females (main effect of exercise, p<0.05). Here we demonstrate that a single bout of exercise stimulates the release of hepatic EVs, with unique and sexually dimorphic proteomic profiles, that are capable of influencing mitochondrial respiration in primary neurons. These data suggest that the liver may mediate exercise induced effects on brain mitochondria through EVs. * MoTrPAC-generated data have undergone preliminary analysis by the authors of this work; results presented here do not represent the final consensus analysis by MoTrPAC. U01AG070928 (The Molecular Transducers of Physical Activity Consortium on behalf of the preclinical animal study sites 2 for the MoTrPAC Study Group) and by FWB, RSR, and JPT. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

While canonical anabolic and proteolytic pathways have been well examined in the context of skeletal muscle proteostasis, the roles of endoplasmic reticulum stress (ERS) and the induced unfolded protein response (UPR) are underappreciated. Thus, we aimed to determine whether aging and/or disuse atrophy in rats altered skeletal muscle ERS/UPR markers. Soleus (SOL) and plantaris (PLT) muscles of 3-month-old (mo), 6 mo, 12 mo, 18 mo, and 24 mo rats (9–10 per group, 48 in total) were analyzed for UPR proteins with further analysis performed on the protein CHOP. The gastrocnemius muscles of 4 mo rats that had undergone hindlimb immobilization (HLI, n = 12) or sham casting (CTL, n = 12) were analyzed for similar targets as well as more extensive CHOP-related targets. CHOP protein was greater in the PLT and SOL of 18 and 24 mo rats versus other age groups (P < 0.05). Moreover, negative correlations existed between CHOP expression and normalized PLT (R=-0.702, P < 0.001) and SOL (R=-0.658, P < 0.001) muscle weights in all rats analyzed at different ages. CHOP protein expression was also greater in the gastrocnemius of HLI versus CTL rats (P < 0.001), and a negative correlation existed between CHOP protein expression and normalized muscle weights in these rats (R=-0.814, P < 0.001). Nuclear CHOP protein levels (P < 0.010) and genes transcriptionally regulated by CHOP were also greater in HLI versus CTL rats (P < 0.001) implicating transcriptional activity of CHOP is elevated during disuse atrophy. CHOP is operative during aging- and disuse-induced skeletal muscle atrophy in rodents, and more research is needed to determine if CHOP is a key mechanistic driver of these processes.

Aging and disuse can impair skeletal muscle responses to stimuli and are key drivers in dysregulated proteostasis. Such dysfunction can lead to an accumulation of misfolded proteins resulting in endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR). While the UPR blunts global translation and enhances the production of chaperones and foldases, little is known about ERS responses across the lifespan and in disuse contexts. Therefore, the purposes of this study were to examine if: i) the expression of ERS and UPR effector proteins differ across the lifespan in rats, and ii) age-associated patterns were recapitulated by 10 days of hindlimb casting in a separate cohort of rats. We hypothesized that aging would enhance the expression of ERS related proteins, and this expression pattern would be mimicked by 10 days of limb disuse. Male Fischer 344 rats were sacrificed at 3, 6, 12, 18, and 24 months (mo) of age, and plantaris (PLT) and soleus (SOL) muscles were collected for analysis. Six mo female Wistar rats were sacrificed after either 10 days of hindlimb casting or continued ambulation (age matched control), after which whole gastrocnemius muscles were collected for analysis. The effector eukaryotic initiation factor 2 alpha (eIF2a) was different across the lifespan (phospho/pan) in PLT and SOL muscles (p<0.001) and was upregulated in the PLT at 24 mo as compared to 3 mo (P=0.006). The downstream UPR effector C/EBP homologous protein (CHOP) was differentially expressed across the lifespan in PLT and SOL (p<0.001). CHOP was upregulated ~2.79 and 3.08-fold at 18 and 24 mo respectively in the SOL (p<0.001), and 2.62 and 2.44-fold at 18 and 24 mo respectively in the PLT. Finally, principal effector Activating Transcription Factor 6 (ATF6) was differentially expressed across the lifespan (cleaved/pan) in the PLT and SOL (P≤0.024) whereby a 1.23-fold up-regulation was evident at 18 mo in the SOL (P=0.035) and 1.34-fold at 18 mo in the PLT (P=0.026). The CHOP and ATF6 proteins were similarly dysregulated in our disuse model, whereby 1.83-fold (p<0.001) and 1.30-fold (P=0.002) greater values were observed in hind limb casted versus control rats. Effectors of the UPR pathway are upregulated in skeletal muscle across the lifespan in rats, and this effect is recapitulated with disuse. These findings warrant further research for potential therapeutics related to age- and disuse-related skeletal muscle atrophy. Funding for this study was provided by discretionary laboratory funds from MDR. This is the full abstract presented at the American Physiology Summit 2024 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.

Alzheimer's disease (AD) is the fifth leading cause of death in older adults, and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a threefold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse [via a model of hindlimb immobilization (HLI)] on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-mo-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of amyloid precursor protein (APP) and tau protein in the hippocampus, 4) and reduced brain-derived neurotrophic factor (BDNF) expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.NEW & NOTEWORTHY Muscle disuse via hindlimb immobilization increased oxidative stress and insulin resistance in the hippocampus. These findings were in association with muscle iron overload in connection with iron dysregulation in the brain. Overall, our work identifies muscle disuse as a contributor to hippocampal dysfunction, potentially through an iron-based muscle-brain axis, highlighting iron dysregulation as a potential novel mechanism in the relationship between muscle health, cognitive function, and Alzheimer's disease risk.

Physical inactivity is the 4th leading cause of death globally and has been shown to significantly increase the risk for developing Alzheimer's Disease (AD). Recent work has demonstrated that exercise prior to breeding produces heritable benefits to the brains of offspring, suggesting that the physical activity status of previous generations could play an important role in one's brain health and their subsequent risk for neurodegenerative diseases. Thus, our study aimed to test the hypothesis that selective breeding for physical inactivity, or for high physical activity, preference produces heritable deficits and enhancements to brain health, respectively. To evaluate this hypothesis, male and female sedentary Low Voluntary Runners (LVR), wild type (WT), and High Voluntary Runner (HVR) rats underwent cognitive behavioral testing, analysis of hippocampal neurogenesis and mitochondrial respiration, and molecular analysis of the dentate gyrus. These analyses revealed that selecting for physical inactivity preference has produced major detriments to cognition, brain mitochondrial respiration, and neurogenesis in female LVR while female HVR display enhancements in brain glucose metabolism and hippocampal size. On the contrary, male LVR and HVR showed very few differences in these parameters relative to WT. Overall, we provide evidence that selective breeding for physical inactivity has a heritable and detrimental effect on brain health and that the female brain appears to be more susceptible to these effects. This emphasizes the importance of remaining physically active as chronic intergenerational physical inactivity likely increases susceptibility to neurodegenerative diseases for both the inactive individual and their offspring.

Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of “work-induced hypertrophy” in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.

Physical inactivity is the 4th leading cause of death globally and has been shown to significantly increase one’s risk for developing Alzheimer’s Disease (AD). A recent study by McGreevy et al. discovered that exercised father rats prior to breeding transfer heritable benefits to the brains of their offspring, suggesting that the physical activity status of previous generations could play an important role in one’s brain health and their subsequent risk for neurodegenerative diseases. Thus, this study aimed to address the effect of intergenerational physical inactivity on brain health. We utilized our selective breeding Wistar rat models of physical inactivity preference, termed Low Voluntary Runners (LVR), and high physical activity preference, High Voluntary Runners (HVR). We hypothesized that LVR would display cognitive deficits and an AD-like phenotype due to selecting for physical inactivity preference while HVR would demonstrate enhancements in cognition and an added resiliency against AD due to their high physical activity preference. First, we evaluated the animals’ innate cognitive status. Male and female wild-type (WT), LVR, and HVR Wistar rats kept in cages with no wheel access underwent cognitive behavioral testing at 3 months old followed by either mitochondrial respiration analysis via oroboros or molecular analysis of the hippocampus region of the brain via RT-PCR, western blotting, and immunohistochemistry (IHC). Cognitive behavioral testing demonstrated spatial memory deficits in LVR relative to WT; interestingly, these deficits were more prevalent in females than males. Behavioral testing results were associated with reductions in hippocampal mitochondrial respiration in female, but not male, LVR. Immunohistochemistry staining revealed that female LVR had fewer immature neurons in the dentate gyrus region of the hippocampus. This suggests that selecting for physical inactivity preference produced deficits in learning and memory, mitochondrial efficiency, and neurogenesis, all of which are hallmark signs of AD. Additionally, male LVR displayed signs of other AD risk factors like insulin resistance and obesity while female LVR appeared to be resistant to these effects. None of these deficits were present in HVR rats, as they performed as well as, or better than, WT. To the best of our knowledge, these findings provide the first evidence that physical inactivity has a heritable and detrimental effect on cognition, hippocampal plasticity, and insulin sensitivity. This emphasizes the importance of remaining physically active as chronic physical inactivity likely increases one’s susceptibility to neurodegenerative diseases like AD for both the inactive individual and their offspring. Self-funded by Dr. Frank Booth 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.

Understanding the neuro-molecular mechanisms that mediate the quantity of daily physical activity (PA) level is of medical significance, given the tremendous health benefits associated with greater physical activ-ity. Here, we examined the effects of intra-nucleus accumbens (NAc) inhibition of activator protein-1 (AP-1), an important transcriptional factor downstream of cAMP response element binding protein (CREB; a reward-related transcriptional regulator), on voluntary wheel running behavior in wild-type (WT) and low voluntary run-ning (LVR) female rats. Transcriptome analysis of the nucleus accumbens (NAc; a brain region critical for PA reward and motivation) was performed to further determine molecular responses to intra-NAc AP-1 inhibition in these rat lines. Within WT rats, intra-NAc AP-1 inhibition caused a significant decrease in overnight running distance in comparison to control rats (p = 0.009). Transcriptomic and bioinformatic analysis in WT rats identified involvement of gene products that regulate cellular proliferation and development, which were cellular processes regulated by AP-1. In contrast to above decreased WT distances, intra-NAc AP-1 inhibition in LVR rats increased nightly running distance in comparison to LVR control rats (p = 0.0008). Further analysis identified gene prod-ucts that are associated with regulating intracellular Ca2+ homeostasis, calcium ion binding and neuronal excitability. In short, our study aims to gain a comprehensive understanding of transcriptional profile that was due to AP-1 inhibition in NAc, in which it could not only enhance the knowledge regarding molecular regulatory loops within NAc for modulating voluntary running behavior, but also provide further insights into molecular tar-gets for future investigations.& COPY; 2022 Published by Elsevier Ltd on behalf of IBRO.

Physical activity (PA) is a non-invasive, cost-effective means of reducing chronic disease. Most US citizens fail to meet PA guidelines, and individuals experiencing chronic stress are less likely to be physically active. To better understand the barriers to maintaining active lifestyles, we sought to determine the extent to which short- versus long-term PA increases stress- and aversion-related markers in wild-type (WT) and low voluntary running (LVR) rats, a unique genetic model of low physical activity motivation. Here, we tested the effects of 1 and 4 weeks of voluntary wheel-running on physiological, behavioral, and molecular measures of stress and Hypothalamic Pituitary Adrenal (HPA)-axis responsiveness (corticosterone levels, adrenal wet weights, and fecal boli counts). We further determined measures of aversion-related signaling (kappa opioid receptor, dynorphin, and corticotropin releasing hormone mRNA expression) in the basolateral amygdala (BLA), a brain region well characterized for its role in anxiety and aversion. Compared to sedentary values, 1, but not 4 weeks of voluntary wheel-running increased adrenal wet weights and plasma corticosterone levels, suggesting that HPA responsiveness normalizes following long-term PA. BLA mRNA expression of prodynorphin (Pdyn) was significantly elevated in WT and LVR rats following 1 week of wheel-running compared to sedentary levels, suggesting that aversion-related signaling is elevated following short- but not long-term wheel-running. In all, it appears that the stress effects of acute PA may increase molecular markers associated with aversion in the BLA, and that LVR rats may be more sensitive to these effects, providing a potential neural mechanism for their low PA motivation.

OBJECTIVE:Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise-induced hepatic mitochondrial adaptations. METHODS:Here, male and female hepatocyte-specific eNOS knockout (eNOShep-/- ) and intact hepatic eNOS (eNOSfl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks. RESULTS:EX resolved the exacerbated hepatic steatosis in eNOShep-/- male mice. Elevated hydrogen peroxide emission (~50% higher in eNOShep-/- vs. eNOSfl/fl mice) was completely ablated with EX. Interestingly, EX increased [1-14 C] palmitate oxidation in eNOSfl/fl male mice, but this was blunted in the eNOShep-/- male mice. eNOShep-/- mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/phospho- (p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOSfl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α). CONCLUSIONS:Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations.

Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent 3 wk of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed toward the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24 h after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24 h post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as 3 wk. In addition, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.NEW & NOTEWORTHY To further elucidate the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training in rats would attenuate lipopolysaccharide-induced neuroinflammation. Our data demonstrated that resistance training had an anti-inflammatory effect in the brain as LPS-induced neuroinflammatory cytokine expression and reactive astrocytic remodeling were reduced in the dentate gyrus after 3 wk of progressive ladder climbing.

Physical inactivity is the fourth leading global cause of death and is a major contributor to metabolic and endocrine diseases. In this review we provide a current update of the past 5 years in the field as it pertains to the most prevalent and deadly chronic diseases. Despite the prevalence of physical inactivity in modern society, it remains largely overlooked relative to other comparable risk factors such as obesity, and our molecular understanding of how physical inactivity impacts metabolism is still partially unknown. Therefore, we discuss current clinical inactivity models along with their most recent findings regarding health outcomes along with any discrepancies that are present in the field. Lastly, we discuss future directions and the need for translatable animal models of physical inactivity to discover novel molecular targets for the prevention of chronic disease.

Mild cognitive impairment (MCI) designates the boundary area between cognitive function in natural aging and dementia, and this is viewed as a therapeutic window to prevent the occurrence of dementia. The current study investigated the neurocognitive effects of oral creatine (Cr) supplementation in young female Wistar rats that received intracerebroventricular injections of lipopolysaccharide (LPS) to mimic MCI. Neuromolecular changes within the dentate gyrus were analyzed following behavioral testing. We also investigated both neurocognitive and neuromolecular changes following Cr supplementation in the absence of LPS in young female Wistar rats to further investigate mechanisms. Interestingly, based on trial 2 of Barnes maze test, Cr supplementation ameliorated spatial learning and memory deficit induced by LPS, shown by decreased latency time and errors to reach the escape box (p < 0.0001, n = 12). Cr supplementation also attenuated recognition memory deficit induced by LPS, shown by increased amount of time taken to explore the new object (p = 0.002, n = 12) during novel object recognition testing. Within the dentate gyrus, Cr supplementation in LPS injected rats upregulated mTORC1 signaling (p = 0.026 for mTOR phosphorylation, p = 0.002 for p70S6K phosphorylation, n = 8) as well as the synapsin (p = 0.008) and PSD-95 synaptic proteins (p = 0.015), in comparisons to LPS injected rats. However, Cr supplementation failed to further enhance spatial memory and recognition memory in the absence of LPS. In conclusion, Cr ameliorates LPS-induced cognitive impairment in a rodent MCI model. Mechanistically, these phenotypic effects may, in part, be mitigated via an upregulation of mTORC1 signaling, and an enhancement in synaptogenesis in the dentate gyrus. While preliminary, these findings may inform future research investigating neurocognitive effects of Cr for MCI patients.

EditorialA tribute to Charles M. “Tip” Tipton (1927–2021)Jerome A. Dempsey, Ralph F. Fregosi, and Frank W. BoothJerome A. DempseyJohn Rankin Laboratory of Pulmonary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, Ralph F. FregosiDepartment of Physiology, University of Arizona, Tucson, Arizona, and Frank W. BoothDepartment of Biomedical Sciences, University of Missouri, Columbia, MissouriPublished Online:12 Jul 2021https://doi.org/10.1152/japplphysiol.00370.2021This is the final version - click for previous versionMoreSectionsPDF (474 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Charlie Tipton was passionate about all aspects of physiology—its science, teaching, mentoring, students, history, and its professional associations (Fig. 1). Tip was a Depression-era child in Illinois and Maryland and served his country in World War II. After receiving his BS from Springfield College, he taught and coached briefly in high school before returning to complete his PhD in physiology under the tutelage of R.E. Johnson at the University of Illinois in 1962. His academic careers included 21 years at the University of Iowa and 14 years at the University of Arizona. Then, Tip served another 16 years with the National Aeronautics and Space Administration (NASA) research programs concerned with the cardiovascular effects of microgravity and their alleviation through exercise training.Starting in 1963 in Iowa, Tip pioneered a landmark, cross-disciplinary National Institutes of Health (NIH)-supported graduate program in exercise physiology, which emphasized an in-depth education in basic sciences. Students used animal models to investigate mechanisms underlying the effects of physical training and of chronic inactivity and microgravity on cardiovascular regulation, hypertension, renal and endocrine function, and on tendon and ligament structures. In the early days, ongoing activities in Tip’s stadium laboratory in Iowa would routinely consist of rodents and dogs running on treadmills, side-by-side with a dozen Langendorf isolated heart preparations, and in parallel with heated debates on the pathophysiology and ethics of “making weight” in collegiate wrestlers. For many years at Iowa, Tip held “student symposia,” which consisted of visiting scientists participating in debates and providing one-on-one feedback to students over a 2-day period. Charlie cared deeply that his students received in-depth experiences in the scientific process. These programs graduated 30 PhDs and also provided research experiences for many minority high school students and teachers. Tip authored 200 peer-reviewed publications, 45 of which were published in the Journal of Applied Physiology over 5 decades (1966–2016). His progeny have been very successful, contributing another 2,000 research articles providing a prodigious contribution to our understanding of the physiology and pathophysiology of exercise training. His graduate program provided the template for excellence in teaching and research within the discipline of exercise physiology. Then, as chair of the Exercise and Sport Science Department in Tucson his program eventually merged in to a bachelor’s degree in physiology, which became a national model for undergraduate physiology programs. Tip single-handedly developed the Arizona chapter of the APS, with the primary motivation being that “…it is great for the students.”Figure 1.Charles M. Tipton at the University of Arizona. Photograph taken during the late 1990s. Reproduced from Tipton (1) under Creative Commons Attribution CC-BY 4.0 license.Download figureDownload PowerPointContributing to the success of professional organizations such as the American Physiological Society (APS) and the fledgling American College of Sports Medicine (ACSM) were high priorities for Tip. He served and chaired—often for multiple terms—APS committees such as Publications, History, and the Environmental and Exercise Physiology (EEP) section. He was also an APS councilor and Associate Editor for the Journal of Applied Physiology (1988–1997). Importantly, Tip was responsible for reenergizing the History of Physiology within APS, holding annual Experimental Biology (EB) history lectures, as well as establishing the APS Living History program. After retirement, Charlie published several biographies of physiologists and edited two editions of a history of exercise physiology as well as advanced exercise physiology textbooks. Within ACSM, starting in the 1960s, Charlie was the principal architect of the growth of the mechanistic approach to the study of exercise physiology, also serving as the college’s president and editor-in-chief of its journal. Tip dedicated his considerable energies for over 4 decades to improve the quality of almost every aspect of ACSM’s science-based programs.Tip’s dedication to our profession has been recognized by APS (Orr Reynold’s History Award, EEP Honor Award), ACSM (Honor Award and Tipton Student Research Award), American Academy of Kinesiology, and most recently by the Charles Tipton Annual Lectureship at Springfield College. Tip never sought recognition for his own accomplishments; rather, his selfless nature pushed him in the direction of promoting others to be honored. In a 2015 biographical essay, Tip emphasized the significance to him of the 45 annual reunions he had organized to bring together former students and colleagues, because “…to me personal relationships are far more important than scientific findings.”Cited below are brief memories of Tip provided by a few of his former students from the early days at Iowa.“Not only was Charlie a brilliant scientist and mentor, one who provided the foundation for my own successful career, he was also a trusted friend and beloved father figure to me, and I will sorely miss him and our weekly Tuesday chats.”—Ken BaldwinMerle Foss recalls that Tip referred to his first cadre of PhD students as “young turks” and expected them to conduct themselves with a strong presence of professionalism and respect for the scientific method. Who could ever forget his oft-spoken signature position of “just show me the data.”“Dr. Charles Tipton has been a role model of the importance of integrity, humility, knowledge of literature, good experimental design, hard work, and peer review of biomedical science, as well as a model of how to serve the field of exercise physiology, how to continue to be a mentor, and how to be a good friend.”—Harold Laughlin“Dr. Tipton taught me to: 1) better develop my questions for research into exercise mechanisms; 2) practice integrity and honesty in academic research, education, and administration; and 3) respect all types of life.”—Frank BoothCharles is survived by his beloved wife of 68 years, Betty Jane Tipton in Tucson, and by daughters Teresa, Paula, Barbara, Lisa, and Pat. Dr. Charles Tipton enjoyed a long and highly productive life in the service of others. We have lost a leader and a good friend and will miss him greatly.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSJ.A.D. and R.F.F. drafted manuscript; J.A.D., R.F.F., and F.W.B. edited and revised manuscript; J.A.D., R.F.F., and F.W.B. approved final version of manuscript.REFERENCE1. Tipton CM. Career perspective: Charles M Tipton. Extrem Physiol Med 4: 6, 2015. doi:10.1186/s13728-015-0024-y. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESCorrespondence: J. A. Dempsey ([email protected]edu) Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 131Issue 1July 2021Pages 192-193 Crossmark Copyright & PermissionsCopyright © 2021 the American Physiological Society.https://doi.org/10.1152/japplphysiol.00370.2021PubMed34080924History Received 27 May 2021 Accepted 28 May 2021 Published online 12 July 2021 Published in print 1 July 2021 KeywordsDopplerbioimpedancecardiac outputhead up tilt testvalidationPDF download Metrics Downloaded 811 times

Given the integral role of nucleus accumbens (NAc) cAMP response element binding protein (CREB) activity in motivational processes, the goal of the current study was to determine whether blunting chronic NAc CREB activity could rescue the low physical activity motivation of female, low voluntary running (LVR) rats. NAc CREB phosphorylation is elevated in these rats, a state previously attributed to deficits in reward valuation. It was recently shown that overexpression of the upstream CREB inhibitor, protein kinase inhibitor alpha (PKIα), increased LVR nightly running by ~threefold. Therefore, the current study addresses the extent to which NAc CREB attenuation influences female LVR and wild-type (WT) wheel-running behavior. Inducible reductions in NAc neuronal activity using Gi-coupled hM4Di DREADDs increased running behavior in LVR, but not in WT, rats. Similarly, site-directed pharmacological inhibition of NAc CREB activity significantly increased LVR nightly running distance and time by ~twofold, with no effect in WT rats. Finally, environmentally enriched LVR rats exhibit higher levels of running compared to socially isolated rats in what appeared to be a CREB-related manner. Considering the positive outcomes of upstream CREB modulation and environmental enrichment on LVR behavior, we believe that blunting NAc CREB activity has the neuromolecular potential to partially reverse low physical activity motivation, as exemplified by the LVR model. The positive physical activity outcome of early life enrichment adds translatable value to human childhood enrichment and highlights its importance on motivational processes later in life.

A gene was sought that could reverse low voluntary running distances in a model of low voluntary wheel-running behavior. In order to confirm the low motivation to wheel-run in our model does not result from defects in reward valuation, we employed sucrose preference and conditioned place preference for voluntary wheel-access. We observed no differences between our model and wild-type rats regarding the aforementioned behavioral testing. Instead, low voluntary runners seemed to require less running to obtain similar rewards for low voluntary running levels compared to wild-type rats. Previous work in our lab identified protein kinase inhibitor alpha as being lower in low voluntary running than wild-type rats. Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. Utilizing a nucleus accumbens preparation, three intermediate early gene mRNAs increased in low voluntary running slices after dopamine receptor agonist SKF-38393 exposure, while wild-type had no response. In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats.