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    Acute cycling exercise and hippocampal subfield function and microstructure in healthy older adults
    (Wiley, 2023-08-01) Callow, Daniel D.; Kommula, Yash; Stark, Craig E.L.; Smith, J. Carson
    Aging is associated with deterioration in dentate gyrus (DG) and CA3, both crucial hippocampal subfields for age susceptible memory processes such as mnemonic discrimination (MD). Meanwhile, a single aerobic exercise session alters DG/CA3 function and neural activity in both rats and younger adults and can elicit short-term microstructural alterations in the hippocampus of older adults. However, our understanding of the effects of acute exercise on hippocampal subfield integrity via function and microstructure in older adults is limited. Thus, a within subject-design was employed to determine if 20-min of moderate to vigorous aerobic exercise alters bilateral hippocampal subfield function and microstructure using high-resolution functional magnetic resonance imaging (fMRI) during an MD task (n = 35) and high angular resolution multi-shell diffusion imaging (n = 31), in healthy older adults, compared to seated rest. Following the exercise condition, participants exhibited poorer MD performance, particularly when their perception of effort was higher. Exercise was also related to lower MD-related activity within the DG/CA3 but not CA1 subfield. Finally, after controlling for whole brain gray matter diffusion, exercise was associated with lower neurite density index (NDI) within the DG/CA3. However, exercise-related differences in DG/CA3 activity and NDI were not associated with differences in MD performance. Our results suggest moderate to vigorous aerobic exercise may temporarily inhibit MD performance, and suppress DG/CA3 MD-related activity and NDI, potentially through neuroinflammatory/glial processes. However, additional studies are needed to confirm whether these short-term changes in behavior and hippocampal subfield neurophysiology are beneficial and how they might relate to long-term exercise habits.
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    Arterial stiffness and blood pressure are similar in naturally menstruating and oral contraceptive pill-using women during the higher hormone phases
    (Wiley, 2022-02-24) Eagan, Lauren E.; Chesney, Catalina A.; Mascone, Sara E.; Ranadive, Sushant M.
    New Findings What is the central question of this study? Are there differences in blood pressure, arterial stiffness and indices of pressure waveforms between young oral contraceptive pill-using and naturally menstruating women during lower and higher hormone phases of their cycles? What is the main finding and its importance? Blood pressure, arterial stiffness and indices of pressure waveforms are influenced similarly by exogenous and endogenous hormones. However, lower levels of exogenous hormones moderately increase blood pressure among oral contraceptive pill-using women. Elevations in blood pressure (BP) are understood as having a bidirectional relationship with stiffening of central and peripheral arteries. Arterial stiffness is mitigated by oestrogen, which aides in arterial vasorelaxation. To evaluate whether BP, stiffness, and pressure waveforms were different between young healthy naturally menstruating (non-OCP) and oral contraceptive pill (OCP)-using women, we measured brachial and aortic BPs, carotid-to-femoral pulse wave velocity, carotid β-stiffness, elastic modulus, central augmentation index and augmentation index normalized to a heart rate of 75 bpm, and forward and backward pressure waveforms in 22 women (22 (1) years, OCP: n = 12). To assess phasic differences, women were studied during the early follicular (≤5 days of menstruation onset) and early luteal (4 (2) days post-ovulation) phases of non-OCP and compared to the placebo pill (≤5 days of onset) and active pill (≤5 days of highest-dose active pill) phases of OCP. During the lower hormone phases, OCP users had significantly higher brachial systolic blood pressure (SBP) (119.3 (8.3) vs. 110.2 (8.3) mmHg, P = 0.02) and aortic SBP (104.10 (7.44) vs. 96.80 (6.39) mmHg, P = 0.03) as compared to non-OCP users; however, during the higher hormone phases, there were no differences in measures of brachial or aortic BP, arterial stiffness, or indices of BP waveforms between OCP and non-OCP users (P ≥ 0.05). In conclusion, exogenous and endogenous hormones have similar influences on BP and arterial stiffness; however, lower levels of exogenous hormones augment both central and peripheral BPs.
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    Race and sex differences in ROS production and SOD activity in HUVECs
    (PLoS, 2023-10-04) Mascone, Sara E.; Kim, Katherine I.; Evans, William S.; Prior, Steven J.; Cook, Marc D.; Ranadive, Sushant M.
    Black individuals and men are predisposed to an earlier onset and higher prevalence of hypertension, compared with White individuals and women, respectively. Therefore, the influence of race and sex on reactive oxygen species (ROS) production and superoxide dismutase (SOD) activity following induced inflammation was evaluated in female and male human umbilical vein endothelial cells (HUVECs) from Black and White individuals. It was hypothesized that HUVECs from Black individuals and male HUVECs would exhibit greater ROS production and impaired SOD activity. Inflammation was induced in HUVEC cell lines (n = 4/group) using tumor necrosis factor-alpha (TNF-α, 50ng/ml). There were no between group differences in ROS production or SOD activity in HUVECs from Black and White individuals, and HUVECs from Black individuals exhibited similar SOD activity at 24hr compared with 4hr of TNF-α treatment (p>0.05). However, HUVECs from White individuals exhibited significantly greater SOD Activity (p<0.05) at 24hr as compared to 4hr in the control condition but not with TNF-α treatment (p>0.05). Female HUVECs exhibited significantly lower ROS production than male HUVECs in the control condition and following TNF-α induced inflammation (p<0.05). Only female HUVECs exhibited significant increases in SOD activity with increased exposure time to TNF-α induced inflammation (p<0.05). HUVECs from White individuals alone exhibit blunted SOD activity when comparing control and TNF-α conditions. Further, compared to female HUVECs, male HUVECs exhibit a pro-inflammatory state.
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    Physical Activity and Brain Function in Older Adults at Increased Risk for Alzheimer’s Disease
    (MDPI, 2013-01-14) Smith, J. Carson; Nielson, Kristy A.; Woodard, John L.; Seidenberg, Michael; Rao, Stephen M.
    Leisure-time physical activity (PA) and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4) allele, diagnosis of mild cognitive impairment (MCI), or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD.
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    The Influence of Family Dog Ownership and Parental Perceived Built Environment Measures on Children’s Physical Activity within the Washington, DC Area
    (MDPI, 2017-11-16) Roberts, Jennifer D.; Rodkey, Lindsey; Grisham, Cortney; Ray, Rashawn
    Sedentary behavior and physical inactivity are significant contributors to youth obesity in the United States. Neighborhood dog walking is an outlet for physical activity (PA). Therefore, understanding the relationship between built environment, dog ownership, and youth PA is essential. This study examined the influence of dog ownership and parental built environment perceptions on children’s PA in the Washington, D.C. area. In 2014, questionnaires were mailed to 2000 parents to assess family dog ownership; children’s outdoor dog walking or playing; and parental perceived built environment measures. Chi-square analyses examined differences in parental perceived built environment measures between children with and without family dogs. The sample included 144 children (50% female; average-age 9.7 years; 56.3% White; 23.7% African-American; 10.4% Asian-American; 29.9% owned dog). Only 13% and 5.6% of the children walked or played outdoors with the dog daily, respectively. A significantly greater proportion (p-value < 0.05) of parents who owned dogs recognized and observed some home built environment measures (e.g., traffic speed on most streets is 30 mph or less) that were PA -promoting for their children. Findings suggest that dog ownership may provide more positive parental perceptions of the neighborhood built environment, which supports children’s outdoor PA through dog walking and playing.
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    Examining the Influence of a New Light Rail Line on the Health of a Demographically Diverse and Understudied Population within the Washington, D.C. Metropolitan Area: A Protocol for a Natural Experiment Study
    (MDPI, 2018-02-13) Roberts, Jennifer D.; Hu, Ming; Saksvig, Brit Irene; Brachman, Micah L.; Durand, Casey P.
    Approximately two-thirds of adults and youth in Prince George’s County, Maryland, a suburb of Washington, D.C. are overweight or obese and less than half are achieving daily physical activity recommendations. Active transportation (AT), such as walking, biking or using public transportation (PT), is a strategic pathway to improving physical activity levels and thus reducing excess weight. Utilizing an expansion of the Washington, D.C. area transportation system with a new light rail line, the Purple Line Outcomes on Transportation (PLOT) Study will exam pre- and post-Purple Line PT use, AT behaviors and attitudes and physical activity among Prince George’s County adults and youth. The PLOT Study will take advantage of this natural experiment in an area enduring significant racial/ethnic and gender-based overweight or obesity and physical inactivity disparities. While similar natural experiments on AT have been conducted in other U.S. cities, those studies lacked diverse and representative samples. To effectively evaluate these physical activity outcomes among this population, efforts will be used to recruit African American and Latino populations, the first and second most common racial/ethnic groups in Prince George’s County. Finally, the PLOT Study will also examine how contextual effects (e.g., neighborhood built environment) impact PT, AT and physical activity.
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    Between Privilege and Oppression: An Intersectional Analysis of Active Transportation Experiences Among Washington D.C. Area Youth
    (MDPI, 2019-04-12) Roberts, Jennifer D.; Mandic, Sandra; Fryer, Craig S.; Brachman, Micah L.; Ray, Rashawn
    The use of active transportation (AT), such as walking, cycling, or even public transit, as a means of transport offers an opportunity to increase youth physical activity and improve health. Despite the well-known benefits of AT, there are environmental and social variables that converge on the AT experiences of low-income youth and youth of color (YOC) that have yet to be fully uncovered. This study uses an intersectional framework, largely focusing on the race-gender-class trinity, to examine youth AT within a context of transportation inequity. Theoretically guided by the Ecological Model of Active Transportation, focus groups were completed with two groups of girls (15 participants) and two groups of boys (nine participants) ranging between the ages of 12–15 years who lived within the Washington D.C. area. This research found race, gender, and class to be inhibitors of AT for both boys and girls, but with more pronounced negative influences on girls.
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    The Color of Health: Residential Segregation, Light Rail Transit Developments, and Gentrification in the United States
    (MDPI, 2019-09-30) Tehrani, Shadi O.; Wu, Shuling J.; Roberts, Jennifer D.
    As the modern urban–suburban context becomes increasingly problematic with traffic congestion, air pollution, and increased cost of living, city planners are turning their attention to transit-oriented development as a strategy to promote healthy communities. Transit-oriented developments bring valuable resources and improvements in infrastructure, but they also may be reinforcing decades-old processes of residential segregation, gentrification, and displacement of low-income residents and communities of color. Careful consideration of zoning, neighborhood design, and affordability is vital to mitigating the impacts of transit-induced gentrification, a socioeconomic by-product of transit-oriented development whereby the provision of transit service “upscales” nearby neighborhood(s) and displaces existing community members with more affluent and often White residents. To date, the available research and, thus, overall understanding of transit-induced gentrification and the related social determinants of health are limited and mixed. In this review, an overview of racial residential segregation, light rail transit developments, and gentrification in the United States has been provided. Implications for future transit-oriented developments are also presented along with a discussion of possible solutions.
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    Environments, Behaviors, and Inequalities: Reflecting on the Impacts of the Influenza and Coronavirus Pandemics in the United States
    (MDPI, 2020-06-22) Roberts, Jennifer D.; Tehrani, Shadi O.
    In the past century, dramatic shifts in demographics, globalization and urbanization have facilitated the rapid spread and transmission of infectious diseases across continents and countries. In a matter of weeks, the 2019 coronavirus pandemic devastated communities worldwide and reinforced the human perception of frailty and mortality. Even though the end of this pandemic story has yet to unfold, there is one parallel that is undeniable when a comparison is drawn between the 2019 coronavirus and the 1918 influenza pandemics. The public health response to disease outbreaks has remained nearly unchanged in the last 101 years. Furthermore, the role of environments and human behaviors on the effect and response to the coronavirus pandemic has brought to light many of the historic and contemporaneous inequalities and injustices that plague the United States. Through a reflection of these pandemic experiences, the American burden of disparity and disproportionality on morbidity, mortality and overall social determinants of health has been examined. Finally, a reimagination of a post-coronavirus existence has also been presented along with a discussion of possible solutions and considerations for moving forward to a new and better normal.
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    Cardiorespiratory Fitness as a Moderator of Sleep-Related Associations with Hippocampal Volume and Cognition
    (MDPI, 2022-10-07) Alfini, Alfonso J.; Won, Junyeon; Weiss, Lauren R.; Nyhuis, Casandra C.; Zipunnikov, Vadim; Spira, Adam P.; Liu-Ambrose, Teresa; Shackman, Alexander J.; Smith, J. Carson
    The objective of this study was to understand the associations of sleep and cardiorespiratory fitness with hippocampal volume and global cognition among older adults (n = 30, age = 65.8 years, female = 73.3%). Wrist actigraphy provided objective measures of nighttime sleep including sleep duration, average wake bout length (WBL; sleep disturbance), and wake-to-sleep transition probability (WTSP; sleep consolidation). Cardiorespiratory fitness was quantified via cycle exercise using a modified heart rate recovery approach. Magnetic resonance imaging was used to determine hippocampal volume and the Mini-Mental State Examination was used to assess global cognition. Fitness moderated associations of sleep with hippocampal volume and cognitive performance, whereby the association of WBL—an index of poor sleep—with hippocampal atrophy was stronger among less-fit individuals, and the association of sleep duration with cognitive performance was stronger among more-fit individuals. Across the fitness levels, a longer WBL was associated with lower cognitive performance, and a higher WTSP—an index of more consolidated sleep—was associated with greater hippocampal volume. Sleep and fitness were unrelated to the volume of an amygdala control region, suggesting a degree of neuroanatomical specificity. In conclusion, higher cardiorespiratory fitness may attenuate sleep disturbance-related hippocampal atrophy and magnify the cognitive benefits of good sleep. Prospective studies are needed to confirm these findings.
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    Emotional processing and positive affect after acute exercise in healthy older adults
    (Wiley, 2023-06-12) Kommula, Yash; Purcell, Jeremy J.; Callow, Daniel D.; Won, Junyeon; Pena, Gabriel S.; Smith, J. Carson
    The well-elucidated improvement of mood immediately after exercise in older adults presumably involves adaptations in emotion-processing brain networks. However, little is known about effects of acute exercise on appetitive and aversive emotion-related network recruitment in older adults. The purpose of this study was to determine the effect of acute exercise, compared to a seated rest control condition, on pleasant and unpleasant emotion-related regional activation in healthy older adults. Functional MRI data were acquired from 32 active older adults during blocked presentations of pleasant, neutral and unpleasant images from the International Affective Pictures System. fMRI data were collected after participants completed 30 min of moderate to vigorous intensity cycling or seated rest, performed in a counterbalanced order across separate days in a within-subject design. The findings suggest three ways that emotional processing in the brain may be different immediately after exercise (relative to immediately after rest): First, reduced demands on emotional regulation during pleasant emotional processing as indicated by lower precuneus activation for pleasant stimuli; second, reduced processing of negative emotional stimuli in visual association areas as indicated by lower activation for unpleasant stimuli in the bilateral fusiform and ITG; third, an increased recruitment in activation associated with regulating/inhibiting unpleasant emotional processing in the bilateral medial superior frontal gyrus (dorsomedial prefrontal cortex), angular gyri, supramarginal gyri, left cerebellar crus I/II and a portion of right dorsolateral prefrontal cortex. Overall, these findings support that acute exercise in active older adults alters activation in key emotional processing and regulating brain regions.
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    Effects of acute aerobic exercise on mnemonic discrimination performance in older adults
    (Cambridge University Press, 2022-08-15) Callow, Daniel D.; Pena, Gabriel S.; Stark, Craig E. L.; Smith, J. Carson
    Objectives:Ample evidence suggests exercise is beneficial for hippocampal function. Furthermore, a single session of aerobic exercise provides immediate benefits to mnemonic discrimination performance, a highly hippocampal-specific memory process, in healthy younger adults. However, it is unknown if a single session of aerobic exercise alters mnemonic discrimination in older adults, who generally exhibit greater hippocampal deterioration and deficits in mnemonic discrimination performance. Methods: We conducted a within subject acute exercise study in 30 cognitively healthy and physically active older adults who underwent baseline testing and then completed two experimental visits in which they performed a mnemonic discrimination task before and after either 30 min of cycling exercise or 30 min of seated rest. Linear mixed-effects analyses were conducted in which condition order and age were controlled, time (pre vs. post) and condition (exercise vs. rest) were modeled as fixed effects, and subject as a random effect. Results: No significant time by condition interaction effect was found for object recognition (p = .254, η2 =.01), while a significant reduction in interference was found for mnemonic discrimination performance following the exercise condition (p = .012, η2 =.07). A post-intervention only analysis indicated that there was no difference between condition for object recognition (p = .186, η2 =.06), but that participants had better mnemonic discrimination performance (p < .001, η2 =.22) following the exercise. Conclusions: Our results suggest a single session of moderate-intensity aerobic exercise may reduce interference and elicit better mnemonic discrimination performance in healthy older adults, suggesting benefits for hippocampal-specific memory function.
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    Unveiling the neuromechanical mechanisms underlying the synergistic interactions in human sensorimotor system
    (Springer Nature, 2021-01-08) Honarvar, S.; Kim, C.; Diaz-Mercado, Y.; Koh, K.; Kwon, H. J.; Kiemel, T.; Caminita, M.; Hahn, J. O.; Shim, J. K.
    Motor synergies are neural organizations of a set of redundant motor effectors that interact with one another to compensate for each other’s error and ensure the stabilization of a performance variable. Recent studies have demonstrated that central nervous system synergistically coordinates its numerous motor effectors through Bayesian multi-sensory integration. Deficiency in sensory synergy weakens the synergistic interaction between the motor effectors. Here, we scrutinize the neuromechanical mechanism underlying this phenomenon through spectral analysis and modeling. We validate our model-generated results using experimental data reported in the literature collected from participants performing a finger force production task with and without tactile feedback (manipulated through injection of anesthetic in fingers). Spectral analysis reveals that the error compensation feature of synergies occurs only at low frequencies. Modeling suggests that the neurophysiological structures involving short-latency back-coupling loops similar to the well-known Renshaw cells explain the deterioration of synergy due to sensory deprivation.
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    The relationship between ciliary neurotrophic factor (CNTF) genotype and motor unit physiology: preliminary studies
    (Springer Nature, 2005-09-23) Conwit, Robin A; Ling, Shari; Roth, Stephen; Stashuk, Daniel; Hurley, Ben; Ferrell, Robert; Metter, E Jeffrey
    Ciliary neurotrophic factor (CNTF) is important for neuronal and muscle development, and genetic variation in the CNTF gene has been associated with muscle strength. The effect of CNTF on nerve development suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. The purpose of this study is to examine whether CNTF genotype differentially affects motor unit activation in the vastus medialis with increasing isometric force during knee extension. Sixty-nine healthy subjects were genotyped for the presence of the G and A (null) alleles in the CNTF gene (n = 57 G/G, 12 G/A). They were tested using a dynamometer during submaximal isometric knee extension contractions that were from 10–50% of their maximal strength. During the contractions, the vastus medialis was studied using surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP) area and mean firing rates (mFR) from identified motor units. CNTF genotyping was performed using standard PCR techniques from DNA obtained from leucocytes of whole blood samples. The CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The two groups used motor units with different size and activation characteristics with increasing force generation. While G/G subjects tended to utilize larger motor units with increasing force, G/A subjects showed relatively less increase in size by using relatively larger units at lower force levels. At higher force levels, G/A subjects were able to generate more force per motor unit size suggesting more efficient motor unit function with increasing muscle force. Differential motor unit responses were observed between CNTF genotypes at force levels utilized in daily activities.
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    Does visual feedback during walking result in similar improvements in trunk control for young and older healthy adults?
    (Springer Nature, 2013-11-26) Anson, Eric; Rosenberg, Russell; Agada, Peter; Kiemel, Tim; Jeka, John
    Most current applications of visual feedback to improve postural control are limited to a fixed base of support and produce mixed results regarding improved postural control and transfer to functional tasks. Currently there are few options available to provide visual feedback regarding trunk motion while walking. We have developed a low cost platform to provide visual feedback of trunk motion during walking. Here we investigated whether augmented visual position feedback would reduce trunk movement variability in both young and older healthy adults. The subjects who participated were 10 young and 10 older adults. Subjects walked on a treadmill under conditions of visual position feedback and no feedback. The visual feedback consisted of anterior-posterior (AP) and medial-lateral (ML) position of the subject’s trunk during treadmill walking. Fourier transforms of the AP and ML trunk kinematics were used to calculate power spectral densities which were integrated as frequency bins “below the gait cycle” and “gait cycle and above” for analysis purposes. Visual feedback reduced movement power at very low frequencies for lumbar and neck translation but not trunk angle in both age groups. At very low frequencies of body movement, older adults had equivalent levels of movement variability with feedback as young adults without feedback. Lower variability was specific to translational (not angular) trunk movement. Visual feedback did not affect any of the measured lower extremity gait pattern characteristics of either group, suggesting that changes were not invoked by a different gait pattern. Reduced translational variability while walking on the treadmill reflects more precise control maintaining a central position on the treadmill. Such feedback may provide an important technique to augment rehabilitation to minimize body translation while walking. Individuals with poor balance during walking may benefit from this type of training to enhance path consistency during over-ground locomotion.
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    Mitochondrial oxygen consumption deficits in skeletal muscle isolated from an Alzheimer’s disease-relevant murine model
    (Springer Nature, 2014-02-13) Schuh, Rosemary A; Jackson, Kathryn C; Schlappal, Anna E; Spangenburg, Espen E; Ward, Christopher W; Park, Ji H; Dugger, Natalie; Shi, Guo Li; Fishman, Paul S
    Age is considered a primary risk factor for neurodegenerative diseases including Alzheimer’s disease (AD). It is also now well understood that mitochondrial function declines with age. Mitochondrial deficits have been previously assessed in brain from both human autopsy tissue and disease-relevant transgenic mice. Recently it has been recognized that abnormalities of muscle may be an intrinsic aspect of AD and might contribute to the pathophysiology. However, deficits in mitochondrial function have yet to be clearly assessed in tissues outside the central nervous system (CNS). In the present study, we utilized a well-characterized AD-relevant transgenic mouse strain to assess mitochondrial respiratory deficits in both brain and muscle. In addition to mitochondrial function, we assessed levels of transgene-derived amyloid precursor protein (APP) in homogenates isolated from brain and muscle of these AD-relevant animals. We now demonstrate that skeletal muscles isolated from these animals have differential levels of mutant full-length APP depending on muscle type. Additionally, isolated muscle fibers from young transgenic mice (3 months) have significantly decreased maximal mitochondrial oxygen consumption capacity compared to non-transgenic, age-matched mice, with similar deficits to those previously described in brain. This is the first study to directly examine mitochondrial function in skeletal muscle from an AD-relevant transgenic murine model. As with brain, these deficits in muscle are an early event, occurring prior to appearance of amyloid plaques.
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    The SH3 and cysteine-rich domain 3 (Stac3) gene is important to growth, fiber composition, and calcium release from the sarcoplasmic reticulum in postnatal skeletal muscle
    (Springer Nature, 2016-04-11) Cong, Xiaofei; Doering, Jonathan; Mazala, Davi A. G.; Chin, Eva R.; Grange, Robert W.; Jiang, Honglin
    The SH3 and cysteine-rich domain 3 (Stac3) gene is specifically expressed in the skeletal muscle. Stac3 knockout mice die perinatally. In this study, we determined the potential role of Stac3 in postnatal skeletal muscle growth, fiber composition, and contraction by generating conditional Stac3 knockout mice. We disrupted the Stac3 gene in 4-week-old male mice using the Flp-FRT and tamoxifen-inducible Cre-loxP systems. RT-qPCR and western blotting analyses of the limb muscles of target mice indicated that nearly all Stac3 mRNA and more than 70 % of STAC3 protein were deleted 4 weeks after tamoxifen injection. Postnatal Stac3 deletion inhibited body and limb muscle mass gains. Histological staining and gene expression analyses revealed that postnatal Stac3 deletion decreased the size of myofibers and increased the percentage of myofibers containing centralized nuclei, with no effect on the total myofiber number. Grip strength and grip time tests indicated that postnatal Stac3 deletion decreased limb muscle strength in mice. Muscle contractile tests revealed that postnatal Stac3 deletion reduced electrostimulation-induced but not the ryanodine receptor agonist caffeine-induced maximal force output in the limb muscles. Calcium imaging analysis of single flexor digitorum brevis myofibers indicated that postnatal Stac3 deletion reduced electrostimulation- but not caffeine-induced calcium release from the sarcoplasmic reticulum. This study demonstrates that STAC3 is important to myofiber hypertrophy, myofiber-type composition, contraction, and excitation-induced calcium release from the sarcoplasmic reticulum in the postnatal skeletal muscle.
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    Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis
    (Springer Nature, 2017-03-22) Amici, David R.; Pinal-Fernandez, Iago; Mázala, Davi A. G.; Lloyd, Thomas E.; Corse, Andrea M.; Christopher-Stine, Lisa; Mammen, Andrew L.; Chin, Eva R.
    Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.
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    Sensory-to-Motor Overflow: Cooling Foot Soles Impedes Squat Jump Performance
    (Frontiers, 2020-10-09) Caminita, Mia; Garcia, Gina L.; Kwon, Hyun Joon; Miller, Ross H.; Shim, Jae Kun
    Evidence from recent studies on animals and humans suggest that neural overflow from the primary sensory cortex (S1) to the primary motor cortex (M1) may play a critical role in motor control. However, it is unclear if whole-body maximal motor tasks are also governed by this mechanism. Maximum vertical squat jumps were performed by 15 young adults before cooling, then immediately following a 15-min cooling period using an ice-water bath for the foot soles, and finally immediately following a 15-min period of natural recovery from cooling. Jump heights were, on average, 3.1 cm lower immediately following cooling compared to before cooling (p = 3.39 × 10−8) and 1.9 cm lower following natural recovery from cooling (p = 0.00124). The average vertical ground reaction force (vGRF) was also lower by 78.2 N in the condition immediately following cooling compared to before cooling (p = 8.1 × 10−5) and 56.7N lower following natural recovery from cooling (p = 0.0043). The current study supports the S1-to-M1 overflow mechanism in a whole-body dynamic jump.
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    Defects in sarcolemma repair and skeletal muscle function after injury in a mouse model of Niemann-Pick type A/B disease
    (Springer Nature, 2019-01-05) Michailowsky, V.; Li, H.; Mittra, B.; Iyer, S. R.; Mazála, D. A. G.; Corrotte, M.; Wang, Y.; Chin, E. R.; Lovering, R. M.; Andrews, N. W.
    Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Utilizing the NPDA/B mouse model ASM−/− and wild type (WT) littermates, we performed excitation-contraction coupling/Ca2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. ASM−/− flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca2+]i in response to electrical stimulation and early failure in sustaining [Ca2+]i during repeated tetanic contractions. When injured mechanically by needle passage, ASM−/− flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM−/− mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Skeletal muscle fibers from ASM−/− mice have an impairment in intracellular Ca2+ handling that results in reduced Ca2+ mobilization and a more rapid decline in peak Ca2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction-induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease.