SAR: Physical Therapy & Athletic Training: Scholarly Papers

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Predictors of self-perceived stigma in Parkinson’s disease
(Elsevier, 2019) Salazar, Robert D.; Weizenbaum, Emma; Ellis, Terry D.; Earhart, G.M.; Ford, M.P.; Dibble, L.E.; Cronin-Golomb, Alice
OBJECTIVE: The burden of PD extends beyond physical limitations and includes significant psychosocial adjustments as individuals undergo changes to their self-perception and how others perceive them. There is limited quantitative evidence of the factors that contribute to self-perceived stigma, which we addressed in the present study. METHODS: In 362 individuals with PD (157 women, 205 men), self-perceived stigma was measured by the four-item stigma subscale of the Parkinson's Disease Questionnaire (PDQ-39). Hierarchical linear modeling was used to assess predictors of stigma including demographics (age, gender) and disease characteristics: duration, stage (Hoehn & Yahr Scale), motor severity (Unified Parkinson's Disease Rating Scale, UPDRS, Part 3), activities of daily living (UPDRS Part 2), and depression (Geriatric Depression Scale). Predictor variables were chosen based on their significant correlations with the stigma subscale. Further analyses were conducted for men and women separately. RESULTS: For the total sample, the full model accounted for 14% of the variance in stigma perception (p < .001). Younger age and higher depression scores were the only significant predictors (both p < .001). This pattern was also seen for the men in the sample. For the women, only depression was a significant predictor. Depression mediated the relation between stigma and activities of daily living. CONCLUSIONS: Younger age (men) and depression (men and women) were the primary predictors of self-perceived stigma in PD. Disease characteristics (motor and ADL) did not contribute to stigma perception. Depression is a potential treatment target for self-perceived stigma in PD.
Frailty: past, present, and future?
(2021-03) Kwak, Dongmin; Thompson, LaDora V.
The prevalence of frailty across the world in older adults is increasing dramatically and having frailty places a person at increased risk for many adverse health outcomes, including impaired mobility, falls, hospitalizations, and mortality. Globally, the concept of frailty is gaining attention and the scientific field has made great strides in identifying and conceptually defining frailty through consensus conferences, in advancing the overall science of frailty by drawing on basic science discoveries including concepts surrounding the hallmarks of aging, resilience, and intrinsic capacities, and in identifying the many challenges faced by professionals within diverse clinical settings. Currently, it is thought that frailty is preventable, thus the identification of a person's degree of frailty is vital. Identification of frailty is achievable through widely used frailty screening tools, which are valid, reliable, and easy to use. Following the identification of a person's degree of frailty, targeted intervention strategies, such as physical activity programs must be implemented. In this perspective, we provide a historical perspective of the frailty field since the last quarter of the 20th century to present. We identify the proposed underlying pathophysiology of multiple physiological systems, including compromised homeostasis and resilience. Next, we outline the available screening tools for frailty with a physical performance assessment and highlight specific benefits of physical activity. Lastly, we discuss current scientific evidence supporting the physical activity recommendations for the aging population and for older adults with frailty. The goal is to emphasize early detection of frailty and stress the value of physical activity.
Indirect measurement of anterior-posterior ground reaction forces using a minimal set of wearable inertial sensors: from healthy to hemiparetic walking
(2020-06-29) Revi, D.A.; Alvarez, A.M.; Walsh, C.J.; De Rossi, Stefano M.M.; Awad, Louis N.
BACKGROUND: The anterior-posterior ground reaction force (AP-GRF) and propulsion and braking point metrics derived from the AP-GRF time series are indicators of locomotor function across healthy and neurological diagnostic groups. In this paper, we describe the use of a minimal set of wearable inertial measurement units (IMUs) to indirectly measure the AP-GRFs generated during healthy and hemiparetic walking. METHODS: Ten healthy individuals and five individuals with chronic post-stroke hemiparesis completed a 6-minute walk test over a walking track instrumented with six forceplates while wearing three IMUs securely attached to the pelvis, thigh, and shank. Subject-specific models driven by IMU-measured thigh and shank angles and an estimate of body acceleration provided by the pelvis IMU were used to generate indirect estimates of the AP-GRF time series. Propulsion and braking point metrics (i.e., peaks, peak timings, and impulses) were extracted from the IMU-generated time series. Peaks and impulses were expressed as % bodyweight (%bw) and peak timing was expressed as % stance phase (%sp). A 75%-25% split of 6-minute walk test data was used to train and validate the models. Indirect estimates of the AP-GRF time series and point metrics were compared to direct measurements made by the forceplates. RESULTS: Indirect measurements of the AP-GRF time series approximated the direct measurements made by forceplates, with low error and high consistency in both the healthy (RMSE= 4.5%bw; R2= 0.93) and post-stroke (RMSE= 2.64%bw; R2= 0.90) cohorts. In the healthy cohort, the average errors between indirect and direct measurements of the peak propulsion magnitude, peak propulsion timing, and propulsion impulse point estimates were 2.37%bw, 0.67%sp, and 0.43%bw. In the post-stroke cohort, the average errors for these point estimates were 1.07%bw, 1.27%sp, and 0.31%bw. Average errors for the braking estimates were higher, but comparable. CONCLUSIONS: Accurate estimates of AP-GRF metrics can be generated using three strategically mounted IMUs and subject-specific calibrations. This study advances the development of point-of-care diagnostic systems that can catalyze the routine assessment and management of propulsion and braking locomotor deficits during rehabilitation.
The ReWalk ReStore™ soft robotic exosuit: a multi-site clinical trial of the safety, reliability, and feasibility of exosuit-augmented post-stroke gait rehabilitation
(2020-06-18) Awad, Louis N.; Esquenazi, A.; Francisco, G.E.; Nolan, K.J.; Jayaraman, A.
BACKGROUND: Atypical walking in the months and years after stroke constrain community reintegration and reduce mobility, health, and quality of life. The ReWalk ReStore™ is a soft robotic exosuit designed to assist the propulsion and ground clearance subtasks of post-stroke walking by actively assisting paretic ankle plantarflexion and dorsiflexion. Previous proof-of-concept evaluations of the technology demonstrated improved gait mechanics and energetics and faster and farther walking in users with post-stroke hemiparesis. We sought to determine the safety, reliability, and feasibility of using the ReStore™ during post-stroke rehabilitation. METHODS: A multi-site clinical trial (NCT03499210) was conducted in preparation for an application to the United States Food and Drug Administration (FDA). The study included 44 users with post-stroke hemiparesis who completed up to 5 days of training with the ReStore™ on the treadmill and over ground. In addition to primary and secondary endpoints of safety and device reliability across all training activities, an exploratory evaluation of the effect of multiple exposures to using the device on users' maximum walking speeds with and without the device was conducted prior to and following the five training visits. RESULTS: All 44 study participants completed safety and reliability evaluations. Thirty-six study participants completed all five training days. No device-related falls or serious adverse events were reported. A low rate of device malfunctions was reported by clinician-operators. Regardless of their reliance on ancillary assistive devices, after only 5 days of walking practice with the device, study participants increased both their device-assisted (Δ: 0.10 ± 0.03 m/s) and unassisted (Δ: 0.07 ± 0.03 m/s) maximum walking speeds (P's < 0.05). CONCLUSIONS: When used under the direction of a licensed physical therapist, the ReStore™ soft exosuit is safe and reliable for use during post-stroke gait rehabilitation to provide targeted assistance of both paretic ankle plantarflexion and dorsiflexion during treadmill and overground walking. TRIAL REGISTRATION: NCT03499210. Prospectively registered on March 28, 2018.
These legs were made for propulsion: advancing the diagnosis and treatment of post-stroke propulsion deficits
(2020-10-21) Awad, Louis N.; Lewek, M.D.; Kesar, T.M.; Franz, J.R.; Bowden, M.G.
Advances in medical diagnosis and treatment have facilitated the emergence of precision medicine. In contrast, locomotor rehabilitation for individuals with acquired neuromotor injuries remains limited by the dearth of (i) diagnostic approaches that can identify the specific neuromuscular, biomechanical, and clinical deficits underlying impaired locomotion and (ii) evidence-based, targeted treatments. In particular, impaired propulsion by the paretic limb is a major contributor to walking-related disability after stroke; however, few interventions have been able to target deficits in propulsion effectively and in a manner that reduces walking disability. Indeed, the weakness and impaired control that is characteristic of post-stroke hemiparesis leads to heterogeneous deficits that impair paretic propulsion and contribute to a slow, metabolically-expensive, and unstable gait. Current rehabilitation paradigms emphasize the rapid attainment of walking independence, not the restoration of normal propulsion function. Although walking independence is an important goal for stroke survivors, independence achieved via compensatory strategies may prevent the recovery of propulsion needed for the fast, economical, and stable gait that is characteristic of healthy bipedal locomotion. We posit that post-stroke rehabilitation should aim to promote independent walking, in part, through the acquisition of enhanced propulsion. In this expert review, we present the biomechanical and functional consequences of post-stroke propulsion deficits, review advances in our understanding of the nature of post-stroke propulsion impairment, and discuss emerging diagnostic and treatment approaches that have the potential to facilitate new rehabilitation paradigms targeting propulsion restoration.
Design of the WHIP-PD study: a phase II, twelve-month, dual-site, randomized controlled trial evaluating the effects of a cognitive-behavioral approach for promoting enhanced walking activity using mobile health technology in people with Parkinson-disease
(2020-04-20) Rawson, K.S.; Cavanaugh, James T.; Colon-Semenza, Cristina; DeAngelis, T.; Duncan, Ryan P.; Fulford, Daniel; LaValley, Michael P.; Mazzoni, P.; Nordahl, T.; Quintiliani, Lisa M.; Saint-Hilaire, Marie-Helene; Thomas, Cathi A.; Earhart, Gammon M.; Ellis, Theresa D.
BACKGROUND: Parkinson disease (PD) is a debilitating and chronic neurodegenerative disease resulting in ambulation difficulties. Natural walking activity often declines early in disease progression despite the relative stability of motor impairments. In this study, we propose a paradigm shift with a "connected behavioral approach" that targets real-world walking using cognitive-behavioral training and mobile health (mHealth) technology. METHODS/DESIGN: The Walking and mHealth to Increase Participation in Parkinson Disease (WHIP-PD) study is a twelve-month, dual site, two-arm, randomized controlled trial recruiting 148 participants with early to mid-stage PD. Participants will be randomly assigned to connected behavioral or active control conditions. Both conditions will include a customized program of goal-oriented walking, walking-enhancing strengthening exercises, and eight in-person visits with a physical therapist. Participants in the connected behavioral condition also will (1) receive cognitive-behavioral training to promote self-efficacy for routine walking behavior and (2) use a mHealth software application to manage their program and communicate remotely with their physical therapist. Active control participants will receive no cognitive-behavioral training and manage their program on paper. Evaluations will occur at baseline, three-, six-, and twelve-months and include walking assessments, self-efficacy questionnaires, and seven days of activity monitoring. Primary outcomes will include the change between baseline and twelve months in overall amount of walking activity (mean number of steps per day) and amount of moderate intensity walking activity (mean number of minutes per day in which > 100 steps were accumulated). Secondary outcomes will include change in walking capacity as measured by the six-minute walk test and ten-meter walk test. We also will examine if self-efficacy mediates change in amount of walking activity and if change in amount of walking activity mediates change in walking capacity. DISCUSSION: We expect this study to show the connected behavioral approach will be more effective than the active control condition in increasing the amount and intensity of real-world walking activity and improving walking capacity. Determining effective physical activity interventions for persons with PD is important for preserving mobility and essential for maintaining quality of life. Clinical trials registration NCT03517371, May 7, 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03517371. Date of registration: May 7, 2018. Protocol version: Original.
Factors affecting antimicrobial activity of MUC7 12-mer, a human salivary mucin-derived peptide
(2007-11-11) Wei, Guo-Xian; Campagna, Alexander N.; Bobek, Libuse A.
BACKGROUND: MUC7 12-mer (RKSYKCLHKRCR), a cationic antimicrobial peptide derived from the human low-molecular-weight salivary mucin MUC7, possesses potent antimicrobial activity in vitro. In order to evaluate the potential therapeutic application of the MUC7 12-mer, we examined the effects of mono- and divalent cations, EDTA, pH, and temperature on its antimicrobial activity. METHODS: Minimal Inhibitory Concentrations (MICs) were determined using a liquid growth inhibition assay in 96-well microtiter plates. MUC7 12-mer was added at concentrations of 1.56-50 microM. MICs were determined at three endpoints: MIC-0, MIC-1, and MIC-2 (the lowest drug concentration showing 10%, 25% and 50% of growth, respectively). To examine the effect of salts or EDTA, a checkerboard microdilution technique was used. Fractional inhibitory concentration index (FICi) was calculated on the basis of MIC-0. The viability of microbial cells treated with MUC7 12-mer in the presence of sodium or potassium was also determined by killing assay or flow cytometry. RESULTS: The MICs of MUC7 12-mer against organisms tested ranged from 6.25-50 microM. For C. albicans, antagonism (FICi 4.5) was observed for the combination of MUC7 12-mer and calcium; however, there was synergism (FICi 0.22) between MUC7 12-mer and EDTA, and the synergism was retained in the presence of calcium at its physiological concentration (1-2 mM). No antagonism but additivity or indifference (FICi 0.55-2.5) was observed for the combination of MUC7 12-mer and each K+, Na+, Mg2+, or Zn2+. MUC7 12-mer peptide (at 25 microM) also exerted killing activity in the presence of NaCl, (up to 25 mM for C. albicans and up to 150 mM for E. coli, a physiological concentration of sodium in the oral cavity and serum, respectively) and retained candidacidal activity in the presence of KCl (up to 40 mM). The peptide exhibited higher inhibitory activity against C. albicans at pH 7, 8, and 9 than at pH 5 and 6, and temperature up to 60 degrees C did not affect the activity. CONCLUSION: MUC7 12-mer peptide is effective anticandidal agent at physiological concentrations of variety of ions in the oral cavity. These results suggest that, especially in combination with EDTA, it could potentially be applied as an alternative therapeutic agent for the treatment of human oral candidiasis.
Gluten degrading enzymes for treatment of celiac disease
(2020-07-15) Wei, Guoxian; Helmerhorst, Eva J.; Darwish, Ghassan M.; Blumenkranz, Gabriel; Schuppan, Detlef
Celiac disease (CeD) affects about 1% of most world populations. It presents a wide spectrum of clinical manifestations, ranging from minor symptoms to mild or severe malabsorption, and it may be associated with a wide variety of autoimmune diseases. CeD is triggered and maintained by the ingestion of gluten proteins from wheat and related grains. Gluten peptides that resist gastrointestinal digestion are antigenically presented to gluten specific T cells in the intestinal mucosa via HLA-DQ2 or HLA-DQ8, the necessary genetic predisposition for CeD. To date, there is no effective or approved treatment for CeD other than a strict adherence to a gluten-free diet, which is difficult to maintain in professional or social environments. Moreover, many patients with CeD have active disease despite diet adherence due to a high sensitivity to traces of gluten. Therefore, safe pharmacological treatments that complement the gluten-free diet are urgently needed. Oral enzyme therapy, employing gluten-degrading enzymes, is a promising therapeutic approach. A prerequisite is that such enzymes are active under gastro-duodenal conditions, quickly neutralize the T cell activating gluten peptides and are safe for human consumption. Several enzymes including prolyl endopeptidases, cysteine proteases and subtilisins can cleave the human digestion-resistant gluten peptides in vitro and in vivo. Examples are several prolyl endopeptidases from bacterial sources, subtilisins from Rothia bacteria that are natural oral colonizers and synthetic enzymes with optimized gluten-degrading activities. Without exception, these enzymes must cleave the otherwise unusual glutamine and proline-rich domains characteristic of antigenic gluten peptides. Moreover, they should be stable and active in both the acidic environment of the stomach and under near neutral pH in the duodenum. This review focuses on those enzymes that have been characterized and evaluated for the treatment of CeD, discussing their origin and activities, their clinical evaluation and challenges for therapeutic application. Novel developments include strategies like enteric coating and genetic modification to increase enzyme stability in the digestive tract.
Short-term ONX-0914 administration: performance and muscle phenotype in Mdx mice
(2020-07-19) Kwak, Dongmin; Wei, Guoxian; Thompson, LaDora V.; Kim, Jong-Hee
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. Although the lack of dystrophin protein is the primary defect responsible for the development of DMD, secondary disease complications such as persistent inflammation contribute greatly to the pathogenesis and the time-dependent progression of muscle destruction. The immunoproteasome is a potential therapeutic target for conditions or diseases mechanistically linked to inflammation. In this study, we explored the possible effects of ONX-0914 administration, an inhibitor specific for the immunoproteasome subunit LMP7 (ß5i), on motor performance, muscular pathology and protein degradation in 7-week old MDX mice, an age when the dystrophic muscles show extensive degeneration and regeneration. ONX-0914 (10 mg/kg) was injected subcutaneously on Day 2, 4, and 6. The mice were evaluated for physical performance (walking speed and strength) on Day 1 and 8. We show that this short-term treatment of ONX-0914 in MDX mice did not alter strength nor walking speed. The physical performance findings were consistent with no change in muscle inflammatory infiltration, percentage of central nuclei and proteasome content. Taken together, muscle structure and function in the young adult MDX mouse model are not altered with ONX-0914 treatment, indicating the administration of ONX-0914 during this critical time period does not exhibit any detrimental effects and may be an effective treatment of secondary complications of muscular dystrophy after further investigations.
Commensal bacterium Rothia aeria degrades and detoxifies gluten via a highly effective subtilisin enzyme
(2020-12-02) Wei, Guoxian; Darwish, Ghassan M.; Oppenheim, Frank G.; Schuppan, Detlef; Helmerhorst, Eva J.
Celiac disease is characterized by a chronic immune-mediated inflammation of the small intestine, triggered by gluten contained in wheat, barley, and rye. Rothia aeria, a gram-positive natural colonizer of the oral cavity and the upper digestive tract is able to degrade and detoxify gluten in vitro. The objective of this study was to assess gluten-degrading activity of live and dead R. aeria bacteria in vitro, and to isolate the R. aeria gluten-degrading enzyme. METHODS: After an overnight fast, Balb/c mouse were fed a 1 g pellet of standard chow containing 50% wheat (and 4% gliadin) with or without 1.6 × 107 live R. aeria bacteria. After 2 h, in vivo gluten degradation was assessed in gastric contents by SDS-PAGE and immunoblotting, and immunogenic epitope neutralization was assessed with the R5 gliadin ELISA assay. R. aeria enzyme isolation and identification was accomplished by separating proteins in the bacterial cell homogenate by C18 chromatography followed by gliadin zymography and mass spectrometric analysis of excised bands. RESULTS: In mice fed with R. aeria, gliadins and immunogenic epitopes were reduced by 20% and 33%, respectively, as compared to gluten digested in control mice. Killing of R. aeria bacteria in ethanol did not abolish enzyme activity associated with the bacteria. The gluten degrading enzyme was identified as BAV86562.1, here identified as a member of the subtilisin family. CONCLUSION: This study shows the potential of R. aeria to be used as a first probiotic for gluten digestion in vivo, either as live or dead bacteria, or, alternatively, for using the purified R. aeria enzyme, to benefit the gluten-intolerant patient population.
Identification of pseudolysin (lasB) as an aciduric gluten-degrading enzyme with high therapeutic potential for celiac disease
(Wolters Kluwer Health, Inc., 2015-06) Wei, Guoxian; Tian, Na; Valery, Adriana C.; Zhong, Yi; Schuppan, Detlef; Helmerhorst, Eva J.
OBJECTIVES: Immunogenic gluten proteins implicated in celiac disease (CD) largely resist degradation by human digestive enzymes. Here we pursued the isolation of gluten-degrading organisms from human feces, aiming at bacteria that would digest gluten under acidic conditions, as prevails in the stomach. METHODS: Bacteria with gluten-degrading activities were isolated using selective gluten agar plates at pH 4.0 and 7.0. Proteins in concentrated bacterial cell sonicates were separated by diethylaminoethanol chromatography. Enzyme activity was monitored with chromogenic substrates and gliadin zymography. Elimination of major immunogenic gluten epitopes was studied with R5 and G12 enzyme-linked immunosorbent assays. RESULTS: Gliadin-degrading enzyme activities were observed for 43 fecal isolates, displaying activities in the ~150-200 and <50 kDa regions. The active strains were identified as Pseudomonas aeruginosa. Gliadin degradation in gel was observed from pH 2.0 to 7.0. Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis identified the enzyme as pseudolysin (lasB), a metalloprotease belonging to the thermolysin (M4) family proteases. Its electrophoretic mobility in SDS-polyacrylamide gel electrophoresis and gliadin zymogram gels was similar to that of a commercial lasB preparation, with tendency of oligomerization. Pseudolysin eliminated epitopes recognized by the R5 antibody, while those detected by the G12 antibody remained intact, despite destruction of the nearby major T-cell epitope QPQLPY. CONCLUSIONS: Pseudolysin was identified as an enzyme cleaving gluten effectively at extremely low as well as near-neutral pH values. The potential to degrade gluten during gastric transport opens possibilities for its application as a novel therapeutic agent for the treatment of CD.
Pharmaceutically modified subtilisins withstand acidic conditions and effectively degrade gluten in vivo
(Nature Publishing Group, 2019-05-16) Darwish, Ghassan M.; Helmerhorst, Eva J.; Schuppan, Detlef; Oppenheim, Frank G.; Wei, Guoxian
Detoxification of gluten immunogenic epitopes is a promising strategy for the treatment of celiac disease. Our previous studies have shown that these epitopes can be degraded in vitro by subtilisin enzymes derived from Rothia mucilaginosa, a natural microbial colonizer of the oral cavity. The challenge is that the enzyme is not optimally active under acidic conditions as encountered in the stomach. We therefore aimed to protect and maintain subtilisin-A enzyme activity by exploring two pharmaceutical modification techniques: PEGylation and Polylactic glycolic acid (PLGA) microencapsulation. PEGylation of subtilisin-A (Sub-A) was performed by attaching methoxypolyethylene glycol (mPEG, 5 kDa). The PEGylation protected subtilisin-A from autolysis at neutral pH. The PEGylated Sub-A (Sub-A-mPEG) was further encapsulated by PLGA. The microencapsulated Sub-A-mPEG-PLGA showed significantly increased protection against acid exposure in vitro. In vivo, gluten immunogenic epitopes were decreased by 60% in the stomach of mice fed with chow containing Sub-A-mPEG-PLGA (0.2mg Sub-A/ g chow) (n=9) compared to 31.9 % in mice fed with chow containing unmodified Sub-A (n=9). These results show that the developed pharmaceutical modification can protect Sub-A from auto-digestion as well as from acid inactivation, thus rendering the enzyme more effective for applications in vivo.
Home-based physical therapy with an interactive computer vision system
(2019-10-28) Gu, Yiwen; Pandit, Shreya; Saraee, Elham; Nordahl, Timothy; Ellis, Terry D.; Betke, Margrit
In this paper, we present ExerciseCheck. ExerciseCheck is an interactive computer vision system that is sufficiently modular to work with different sources of human pose estimates, i.e., estimates from deep or traditional models that interpret RGB or RGB-D camera input. In a pilot study, we first compare the pose estimates produced by four deep models based on RGB input with those of the MS Kinect based on RGB-D data. The results indicate a performance gap that required us to choose the MS Kinect when we tested ExerciseCheck with Parkinson’s disease patients in their homes. ExerciseCheck is capable of customizing exercises, capturing exercise information, evaluating patient performance, providing therapeutic feedback to the patient and the therapist, checking the progress of the user over the course of the physical therapy, and supporting the patient throughout this period. We conclude that ExerciseCheck is a user-friendly computer vision application that can assist patients by providing motivation and guidance to ensure correct execution of the required exercises. Our results also suggest that while there has been considerable progress in the field of pose estimation using deep learning, current deep learning models are not fully ready to replace RGB-D sensors, especially when the exercises involved are complex, and the patient population being accounted for has to be carefully tracked for its “active range of motion.”
Are the 10 meter and 6 minute walk tests redundant in patients with spinal cord injury?
(Public Library of Science, 2014-05-01) Forrest, Gail F.; Hutchinson, Karen; Lorenz, Douglas J.; Buehner, Jeffrey J.; VanHiel, Leslie R.; Sisto, Sue Ann; Basso, D. Michele
Downhill exercise alters immunoproteasome content in mouse skeletal muscle
(Springer, 2018-07-01) Baumann, Cory W.; Kwak, Dongmin; Ferrington, Deborah A.; Thompson, LaDora V.
Content of the immunoproteasome, the inducible form of the standard proteasome, increases in atrophic muscle suggesting it may be associated with skeletal muscle remodeling. However, it remains unknown if the immunoproteasome responds to stressful situations that do not promote large perturbations in skeletal muscle proteolysis. The purpose of this study was to determine how an acute bout of muscular stress influences immunoproteasome content. To accomplish this, wildtype (WT) and immunoproteasome knockout lmp7-/-/mecl1-/-(L7M1) mice were run downhill on a motorized treadmill. Soleus muscles were excised 1 and 3 days post-exercise and compared to unexercised muscle(control). Ex vivophysiology, histology and biochemical analyses were used to assess the effects of immunoproteasome knockout and unaccustomed exercise. Besides L7M1 muscle being LMP7/MECL1deficient, no other major biochemical, histological or functional differences were observed between the control muscles. In both strains, the downhill run shifted the force-frequency curve to the right and reduced twitch force, however did not alter tetanic force or inflammatory markers. In the days post-exercise, several of the proteasome 's catalytic subunits were upregulated. Specifically, WT muscle increased LMP7 while L7M1 muscle instead increased ≤ 5. These findings indicate that running mice downhill results in subtle contractile characteristics that correspond to skeletal muscle injury, yet does not appear to induce a significant inflammatory response. Interestingly, this minor stress activated the production of specific immunoproteasome subunits; that if knocked out, were replaced by components of the standard proteasome. These data suggest that the immunoproteasome may be involved in maintaining cellular homeostasis.
Novel individualized power training protocol preserves physical function in adult and older mice
(Springer Nature Switzerland AG, 2019-04) Graber, Ted G.; Fandrey, Katie R.; Thompson, LaDora V.
Sarcopenia, the age-related loss of muscle mass and strength, contributes to frailty, functional decline, and reduced quality of life in older adults. Exercise is a recognized therapy for sarcopenia and muscle dysfunction, though not a cure. Muscle power declines at an increased rate compared to force, and force output declines earlier than mass. Thus, there is a need for research of exercise focusing on improving power output and functionality in older adults. Our primary purpose was proof-of-concept that a novel individualized power exercise modality would induce positive adaptations in adult mice, before the exercise program was applied to an aged cohort. We hypothesized that after following our protocol, both adult and older mice would show improved function, though there would be evidence of anabolic resistance in the older mice. Male C57BL/6 mice (12 months of age at study conclusion) were randomized into control (n = 9) and exercise (n = 6) groups. The trained group used progressive resistance (with a weighted harness) and intensity (~ 4-10 rpm) on a custom motorized running wheel. The mice trained similarly to a human workout regimen (4-5 sets/session, 3 sessions/week, for 12 weeks). We determined significant (p < 0.05) positive adaptations post-intervention, including: neuromuscular function (rotarod), strength/endurance (inverted cling grip test), training physiology (force/power output per session), muscle size (soleus mass), and power/velocity of contraction (in vitro physiology). Secondly, we trained a cohort of older male mice (28 months old at conclusion): control (n = 12) and exercised (n = 8). While the older exercised mice did preserve function and gain benefits, they also demonstrated evidence of anabolic resistance.
Lipotoxicity, aging, and muscle contractility: does fiber type matter?
(Springer Science and Business Media LLC, 2019-06) Carter, Christy S.; Justice, Jamie N.; Thompson, LaDora
Sarcopenia is a universal characteristic of the aging process and is often accompanied by increases in whole-body adiposity. These changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are both significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues, such as skeletal muscle, when the oxidative capacity of the adipose tissue itself is exceeded. The redistributed adipose tissue is thought to exert detrimental local effects on the muscle environment given the close proximity. Thus, sarcopenia observed with aging may be better defined in the context of loss of muscle quality rather than loss of muscle quantity per se. In this perspective, we briefly review the age-related physiological changes in cellularity, secretory profiles, and inflammatory status of adipose tissue which drive lipotoxicity (spillover) of skeletal muscle and then provide evidence of how this may affect specific fiber type contractility. We focus on biological contributors (cellular machinery) to contractility for which there is some evidence of vulnerability to lipid stress distinguishing between fiber types.
Increasing myosin light chain 3f (MLC3f) protects against a decline in contractile velocity
(2019) Kim, Jong-Hee; Graber, Ted G.; Liu, Haiming; Asakura, Atsushi; Thompson, LaDora V.
Disuse induces adaptations in skeletal muscle, which lead to muscle deterioration. Hindlimb-unloading (HU) is a well-established model to investigate cellular mechanisms responsible for disuse-induced skeletal muscle dysfunction. In myosin heavy chain (MHC) type IIB fibers HU induces a reduction in contraction speed (Vo) and a reduction in the relative myosin light chain 3f (MLC3f) protein content compared with myosin light chain 1f (MLC1f) protein. This study tested the hypothesis that increasing the relative MLC3f protein content via rAd-MLC3f vector delivery would attenuate the HU-induced decline in Vo in single MHC type IIB fibers. Fischer-344 rats were randomly assigned to one of three groups: control, HU for 7 days, and HU for 7 days plus rAd-MLC3f. The semimembranosus muscles were injected with rAd-MLC3f (3.75 x 1011-5 x 1011 ifu/ml) at four days after the initiation of HU. In single MHC type IIB fibers the relative MLC3f content decreased by 25% (12.00±0.60% to 9.06±0.66%) and Vo was reduced by 29% (3.22±0.14fl/s vs. 2.27±0.08fl/s) with HU compared to the control group. The rAd-MLC3f injection resulted in an increase in the relative MLC3f content (12.26±1.19%) and a concomitant increase in Vo (2.90±0.15fl/s) of MHC type IIB fibers. A positive relationship was observed between the percent of MLC3f content and Vo. Maximal isometric force and specific tension were reduced with HU by 49% (741.45±44.24μN to 379.09±23.77μN) and 33% (97.58±4.25kN/m2 to 65.05±2.71kN/m2), respectively compared to the control group. The rAd-MLC3f injection did not change the HU-induced decline in force or specific tension. Collectively, these results indicate that rAd-MLC3f injection rescues hindlimb unloading-induced decline in Vo in MHC type IIB single muscle fibers.
Identifying characteristics of frailty in female mice using a phenotype assessment tool
(2019-04-08) Kwak, Dongmin; Baumann, Cory W.; Thompson, LaDora V.
Preclinical studies are important in identifying the underlying mechanisms contributing to frailty. Frailty studies have mainly focused on male rodents with little directed at female rodents. Therefore, the purposes of this study were to identify the onset and prevalence of frailty across the life span in female mice, and to determine if frailty predicts mortality. Female C57BL/6 (n = 27) mice starting at 17 months of age were assessed across the life span using a frailty phenotype, which included body weight, walking speed, strength, endurance, and physical activity. The onset of frailty occurred at approximately 17 months (1/27 mice), with the prevalence of frailty increasing thereafter. At 17 months, 11.1% of the mice were pre-frail and by 26 months peaked at 36.9%. The percentage of frail mice progressively increased up to 66.7% at 32 months. Non-frail mice lived to 29 months whereas frail/pre-frail mice lived only to 26 months (p = .04). In closing, using a mouse frailty phenotype, we are able to identify that the prevalence of frailty in female mice increases across the life span and accurately predicts mortality. Together, this frailty phenotype has the potential to yield information about the underlying mechanisms contributing to frailty.
Sex-specific components of frailty in C57BL/6 mice.
(2019-07-29) Baumann, Cory W.; Kwak, Dongmin; Thompson, LaDora V.
Many age-related biochemical, physiological and behavioral changes are known to be sex-specific. However, how sex influences frailty status and mortality risk in frail rodents has yet to be established. The purpose of this study was therefore to characterize sex differences in frail mice across the lifespan. Male (n=29) and female (n=27) mice starting at 17 months of age were assessed using a frailty phenotype adjusted according to sex, which included body weight, walking speed, strength, endurance and physical activity. Regardless of sex, frail mice were phenotypically dysfunctional compared to age-matched non-frail mice, while non-frail females generally possessed a higher body fat percentage and were more physically active than non-frail males (p≤0.05). The prevalence of frailty was greater in female mice at 26 months of age (p=0.05), but if normalized to mean lifespan, no sex differences remained. No differences were detected in the rate of death or mean lifespan between frail male and female mice (p≥0.12). In closing, these data indicate that sexual differences exist in aging C57BL/6 mice and if the frailty criteria are adjusted according to sex, the prevalence of frailty increases across age with frail mice dying early in life, regardless of sex.

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