The anatomical positioning change of retroperitoneal organs in prone and lateral position: an assessment for single-prone position lateral lumbar surgery.

PURPOSE: There are reports that performing lateral lumbar interbody fusion (LLIF) in a prone, single position (single-prone LLIF) can be done safely in the prone position because the retroperitoneal organs reflect anteriorly with gravity. However, only a few study has investigated the safety of single-prone LLIF and retroperitoneal organ positioning in the prone position. We aimed to investigate the positioning of retroperitoneal organs in the prone position and evaluate the safety of single-prone LLIF surgery. METHODS: A total of 94 patients were retrospectively reviewed. The anatomical positioning of the retroperitoneal organs was evaluated by CT in the preoperative supine and intraoperative prone position. The distances from the centre line of the intervertebral body to the organs including aorta, inferior vena cava, ascending and descending colons, and bilateral kidneys were measured for the lumbar spine. An "at risk" zone was defined as distance less than 10 mm anterior from the centre line of the intervertebral body. RESULTS: Compared to supine preoperative CTs, bilateral kidneys at the L2/3 level as well as the bilateral colons at the L3/4 level had statistically significant ventral shift with prone positioning. The proportion of retroperitoneal organs within the at-risk zone ranged from 29.6 to 88.6% in the prone position. CONCLUSIONS: The retroperitoneal organs shifted ventrally with prone positioning. However, the amount of shift was not large enough to avoid risk for organ injuries and substantial proportion of patients had organs within the cage insertion corridor. Careful preoperative planning is warranted when considering single-prone LLIF.

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.

RATIONALE: Impaired myocardial relaxation is an intractable feature of several heart failure (HF) causes. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development. OBJECTIVE: We aimed to determine if the recently identified complex of VASH1/2 (vasohibin 1/2) and SVBP (small vasohibin binding protein) is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF. METHODS AND RESULTS: Transcriptional profiling revealed that VASH1 transcript is >10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1, VASH2, and SVBP, we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction. Knockdown of VASH1 conferred subtle kinetic improvements in nonfailing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes. CONCLUSIONS: VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from patients with HF, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction.

Quantification and characterization of grouped type I myofibers in human aging.

INTRODUCTION: Myofiber type grouping is a histological hallmark of age-related motor unit remodeling. Despite the accepted concept that denervation-reinnervation events lead to myofiber type grouping, the completeness of those conversions remains unknown. METHODS: Type I myofiber grouping was assessed in vastus lateralis biopsies from Young (26 ± 4 years; n = 27) and Older (66 ± 4 years; n = 91) adults. Grouped and ungrouped type I myofibers were evaluated for phenotypic differences. RESULTS: Higher type I grouping in Older versus Young was driven by more myofibers per group (i.e., larger group size) (P < 0.05). In Older only, grouped type I myofibers displayed larger cross-sectional area, more myonuclei, lower capillary supply, and more sarco(endo)plasmic reticulum calcium ATPase I (SERCA I) expression (P < 0.05) than ungrouped type I myofibers. DISCUSSION: Grouped type I myofibers retain type II characteristics suggesting that conversion during denervation-reinnervation events is either progressive or incomplete. Muscle Nerve 57: E52-E59, 2018.

High-Intensity Exercise Acutely Increases Substantia Nigra and Prefrontal Brain Activity in Parkinson's Disease.

BACKGROUND Pathologic alterations in resting-state brain activity patterns exist among individuals with Parkinson's disease (PD). Since physical exercise alters resting-state brain activity in non-PD populations and improves PD symptoms, we assessed the acute effect of exercise on resting-state brain activity in exercise-trained individuals with PD. MATERIAL AND METHODS Resting-state functional magnetic resonance imaging (fMRI) was collected twice for 17 PD participants at the conclusion of an exercise intervention. The acute effect of exercise was examined for PD participants using the amplitude of low frequency fluctuation (ALFF) before and after a single bout of exercise. Correlations of clinical variables (i.e., PDQ-39 quality of life and MDS-UPDRS) with ALFF values were examined for the exercise-trained PD participants. RESULTS An effect of acute exercise was observed as an increased ALFF signal within the right ventromedial prefrontal cortex (PFC), left ventrolateral PFC, and bilaterally within the substantia nigra (SN). Quality of life was positively correlated with ALFF values within the vmPFC and vlPFC. CONCLUSIONS Given the role of the SN and PFC in motor and non-motor symptoms in PD, the acute increases in brain activity within these regions, if repeated frequently over time (i.e., exercise training), may serve as a potential mechanism underlying exercise-induced PD-specific clinical benefits.

Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro.

Resistance exercise training (RT) is the most effective method for increasing skeletal muscle mass in older adults; however, the amount of RT-induced muscle growth is highly variable between individuals. Recent evidence from our laboratory and others suggests ribosome biogenesis may be an important factor regulating RT-induced hypertrophy, and we hypothesized that the extent of hypertrophy is at least partly regulated by the amount of RT-induced ribosome biogenesis. To examine this, 42 older adults underwent 4 wk of RT aimed at inducing hypertrophy of the knee extensors (e.g., 2 sets of squat, leg press, and knee extension, 10-12 repetition maximums, 3 days/wk), and vastus lateralis muscle biopsies were performed pre- and post-RT. Post hoc K-means cluster analysis revealed distinct differences in type II myofiber hypertrophy among subjects. The percent change in type II myofiber size in nonresponders (Non; n = 17) was -7%, moderate responders (Mod; n = 19) +22%, and extreme responders (Xtr; n = 6) +83%. Total muscle RNA increased only in Mod (+9%, P < 0.08) and Xtr (+26%, P < 0.01), and only Xtr increased rRNA content (+40%, P < 0.05) and myonuclei/type II fiber (+32%, P < 0.01). Additionally, Mod and Xtr had a greater increase in c-Myc protein levels compared with Non (e.g., approximately +350 and +250% vs. +50%, respectively, P < 0.05). In vitro studies showed that growth factor-induced human myotube hypertrophy is abolished when rRNA synthesis is knocked down using the Pol I-specific inhibitor CX-5461. Overall, these data implicate ribosome biogenesis as a key process regulating the extent of RT-induced myofiber hypertrophy in older adults.

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury.

Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNFαR, TNFα, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF-κB, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (≈22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNFαR and TWEAK R gene expression and NF-κB signaling (higher TWEAK R and phospho-NF-κB p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-κB signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle.

Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

While elective total hip arthroplasty (THA) for end-stage osteoarthritis (OA) improves pain, mobility function, and quality of life in most cases, a large proportion of patients suffer persistent muscle atrophy, pain, and mobility impairment. Extensive skeletal muscle damage is unavoidable in these surgical procedures, and it stands to reason that poor recovery and long-term mobility impairment among some individuals after THA is linked to failed muscle regeneration and regrowth following surgery and that local muscle inflammation susceptibility (MuIS) is a major contributing factor. Here we present results of two integrated studies. In study 1, we compared muscle inflammation and protein metabolism signaling in elective THA (n=15) vs. hip fracture/trauma (HFX; n=11) vs. nonsurgical controls (CON; n=19). In study 2, we compared two subgroups of THA patients dichotomized into MuIS⁺ (n=7) or MuIS⁻ (n=7) based on muscle expression of TNF-like weak inducer of apoptosis (TWEAK) receptor (Fn14). As expected, HFX demonstrated overt systemic and local muscle inflammation and hypermetabolism. By contrast, no systemic inflammation was detected in elective THA patients; however, local muscle inflammation in the perioperative limb was profound in MuIS⁺ and was accompanied by suppressed muscle protein synthesis compared with MuIS⁻. Muscle from the contralateral limb of MuIS⁺ was unaffected, providing evidence of a true inflammation susceptibility localized to the muscle surrounding the hip with end-stage OA. We suggest MuIS status assessed at the time of surgery may be a useful prognostic index for muscle recovery potential and could therefore provide the basis for a personalized approach to postsurgery rehabilitation.

Mechanosensitivity may be enhanced in skeletal muscles of spinal cord-injured versus able-bodied men.

We investigated the effects of an acute bout of neuromuscular electrical stimulation-induced resistance exercise (NMES-RE) on intracellular signaling pathways involved in translation initiation and mechanical loading-induced muscle hypertrophy in spinal cord-injured (SCI) versus able-bodied (AB) individuals. AB and SCI individuals completed 90 isometric knee extension contractions at 30% of maximum voluntary or evoked contraction, respectively. Muscle biopsies were collected before, and 10 and 60 min after NMES-RE. Protein levels of α7- and ß1-integrin, phosphorylated and total GSK-3α/ß, S6K1, RPS6, 4EBP1, and FAK were assessed by immunoblotting. SCI muscle appears to be highly sensitive to muscle contraction even several years after the injury, and in fact it may be more sensitive to mechanical stress than AB muscle. Heightened signaling associated with muscle mechanosensitivity and translation initiation in SCI muscle may be an attempted compensatory response to offset elevated protein degradation in atrophied SCI muscle. .

Effects of fatigue from resistance training on barbell back squat biomechanics.

Exhaustive resistance training programs that have been previously referred to as extreme conditioning protocols have increased in popularity in military and civilian populations in recent years. However, because of their highly fatiguing nature, proprioception is likely altered during such programs that would significantly affect the safety and efficacy of such programs. Therefore, the purpose of this study was to assess the alterations in movement patterns that result from extreme conditioning protocols and to evaluate if these protocols can be deemed safe and effective. Twelve men (age 24 ± 4.2 years, height 173.1 ± 3.6 cm, weight 76.9 ± 7.8 kg, body fat percentage 9.0 ± 2.2%) and 13 women (age 24.5 ± 3.8 years, height 166.9 ± 8.5 cm, weight 66.1 ± 9.2 kg, body fat percentage 18.6 ± 4.0%) with at least 6 months of resistance training experience involving barbell bench press, barbell deadlift, and barbell back squat performed a highly fatiguing resistance training workout. During the barbell back squat, a 2-dimensional analysis was performed where the knee and hip angles were recorded throughout the 55 repetitions of the workout. At the early stages of the protocol, knee angle was significantly lower in men and in women demonstrating less knee flexion. Also, hip angle was significantly lower early in the program in men and in women, demonstrating a greater forward lean. The technique changes that occur in high repetition sets do not favor optimal strength development and may increase the risk of injury, clearly questioning the safety and efficacy of such resistance training programming. This is likely a display of self-preservation by individuals who are faced with high repetition programs.

Association of Healthy Lifestyle and Incident Polypharmacy.

BACKGROUND: Polypharmacy, commonly defined as taking ≥5 medications, is an undesirable state associated with lower quality of life. Strategies to prevent polypharmacy may be an important priority for patients. We sought to examine the association of healthy lifestyle, a modifiable risk factor, with incident polypharmacy. METHODS: We performed a secondary analysis of the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study, including 15,478 adults aged ≥45 years without polypharmacy at baseline. The primary exposure was healthy lifestyle at baseline as measured by the Healthy Behavior Score (HBS), a cumulative assessment of diet, exercise frequency, tobacco smoking, and sedentary time. HBS ranges from 0-8, whereby 0-2 indicates low HBS, 3-5 indicates moderate HBS, and 6-8 indicates high HBS. We used multinomial logistic regression to examine the association between HBS and incident polypharmacy, survival without polypharmacy, and death. RESULTS: Higher HBS (i.e., healthier lifestyle) was inversely associated with incident polypharmacy after adjusting for sociodemographic and baseline health variables. Compared with participants with low HBS, those with moderate HBS had lower odds of incident polypharmacy (odds ratio [OR] 0.85; 95% confidence interval [CI], 0.73-0.98) and lower odds of dying (OR 0.74; 95% CI, 0.65-0.83). Participants with high HBS had even lower odds of both incident polypharmacy (OR 0.75; 95% CI, 0.64-0.88) and death (OR 0.62; 95% CI, 0.54-0.70). There was an interaction for age, where the association between HBS and incident polypharmacy was most pronounced for participants aged ≤65 years. CONCLUSIONS: Healthier lifestyle was associated with lower risk for incident polypharmacy.

The Impact of the COVID-19 Pandemic on Ambulatory Lumbar Spine Decompression Surgery.

Background Only a few studies have examined the impact of the coronavirus disease 2019 pandemic on spine ambulatory surgeries and changes in trends. Therefore, we investigated trends during the pre-pandemic period and three pandemic stages in patients undergoing lumbar decompression procedures in the ambulatory surgery (AMS) setting. Methodology A total of 2,670 adult patients undergoing one- or two-level lumbar decompression surgery were retrospectively reviewed. Patients were categorized into the following four groups: 1: pre-pandemic (before the pandemic from January 1, 2019, to March 16, 2020); 2: restricted period (when elective surgery was canceled from March 17, 2020, to June 30, 2020); 3: post-restricted 2020 (July 1, 2020, to December 31, 2020, before vaccination); and 4: post-restricted 2021 (January 1, 2021 to December 31, 2021 after vaccination). Simple and multivariable logistic regression analyses as well as retrospective interrupted time series (ITS) analysis were conducted comparing AMS patients in the four periods. Results Patients from the restricted pandemic period were younger and healthier, which led to a shorter length of stay (LOS). The ITS analysis demonstrated a significant drop in mean LOS at the beginning of the restricted period and recovered to the pre-pandemic levels in one year. Multivariable logistic regression analyses indicated that the pandemic was an independent factor influencing the LOS in post-restricted phases. Conclusions As the post-restricted 2020 period itself might be independently influenced by the pandemic, these results should be taken into account when interpreting the LOS of the patients undergoing ambulatory spine surgery in post-restricted phases.

Effects of a competitive wrestling season on body composition, endocrine markers, and anaerobic exercise performance in NCAA collegiate wrestlers.

Few data exist examining the body composition, endocrine, and anaerobic exercise performance changes over a competitive wrestling season. Eighteen NCAA wrestlers were tested for endocrine markers, body composition, hydration, grip strength, and power on four occasions: prior to pre-season training (T1); after pre-season training 3 days prior to the first seasonal meet (T2); mid-season one day prior to a meet (T3); and at the end of the season 2-3 days following the last meet (T4). Body mass, percent body fat (BF %), and fat mass were significantly lower (P ≤ 0.05) at T2 and T3 compared to T1 but were not different between T1 and T4. Lean body mass was significantly reduced at T2 only. Urine specific gravity was significantly elevated at T3 compared to T1, T2, and T4. Resting cortisol concentrations did not change but resting testosterone concentrations were significantly reduced at T2, T3, and T4. Maximal grip strength was significantly reduced at T2. Vertical jump peak power was significantly reduced at T2, T3, and T4. Wingate peak power was significantly reduced at T2 and T3. However, Wingate average power and total work did not significantly change. Fatigue rate during the Wingate test was significantly improved at T2, T3, and T4 compared to T1. In conclusion, body mass, BF %, and measures of peak force and power were reduced for most of the competitive wrestling season. Competitive wrestling reduces resting total testosterone concentrations throughout the entire season.

Effects of resistance training fatigue on joint biomechanics.

Resistance training has been found to have a multitude of benefits. However, when performed with short rest, resistance training can result in substantial fatigue, which may have a negative impact on exercise technique. The purpose of this study is to examine the effects of fatigue from resistance exercise on joint biomechanics to determine what residual movement effects may exist after the workout. Twelve men with at least 6 months of resistance training experience (age 24 ± 4.2 years, height 173.1 ± 3.6 cm, weight 76.9 ± 7.8 kg) performed 5 body weight squats before (pretest) and after (posttest) a highly fatiguing resistance training workout. Lower extremity biomechanics were assessed using a 3-dimensional motion analysis system during these squats. Peak angle, total displacement, and rate were assessed for knee flexion, trunk flexion, hip flexion, hip rotation, and hip adduction. Results showed a significant decrease in peak angle for knee flexion (Pre: 120.28 ± 11.93°, Post: 104.46 ± 9.85°), hip flexion (Pre: -109.42 ± 12.49°, Post: -95.8 ± 12.30°), and hip adduction (Pre: -23.32 ± 7.04°, Post: -17.30 ± 8.79°). There was a significant reduction in angular displacement for knee flexion (Pre: 115.56 ± 10.55°, Post: 103.35 ± 10.49°), hip flexion (Pre: 97.94 ± 10.69°, Post: 90.51 ± 13.22°), hip adduction (Pre: 17.79 ± 7.36°, Post: 11.89 ± 4.34°), and hip rotation (Pre: 30.72 ± 12.28, Post: 20.48 ± 10.12). There was also a significant reduction in displacement rate for knee flexion (Pre: 2.20 ± 0.20, Post: 1.98 ± 0.20), hip flexion (Pre: 1.92 ± 0.20, Post: 1.76 ± 0.27), hip adduction (Pre: -0.44 ± 0.17, Post: -0.31 ± 0.17), and hip rotation (Pre: 0.59 ± 0.23, Post: 0.38 ± 0.21). This study demonstrated that there are lasting residual effects on movement capabilities after a high-intensity short rest protocol. Thus, strength and conditioning coaches must be careful to monitor movements and exercise techniques after such workouts to prevent injury and optimize subsequent exercise protocols that might be sequenced in order.

Risk Factors for Ambulatory Surgery Conversion to Extended Stay Among Patients Undergoing One-level or Two-level Posterior Lumbar Decompression.

STUDY DESIGN: A retrospective observational study. OBJECTIVE: The objective of this study was to investigate the factors associated with the conversion of patient status from ambulatory surgery (AMS) to observation service (OS) (<48 h) or inpatient (>48 h). SUMMARY OF BACKGROUND DATA: AMS is becoming increasingly common in the United States because it is associated with a similar quality of care compared with inpatient surgery, significant costs reduction, and patients' desire to recuperate at home. However, there are instances when AMS patients may be subjected to extended hospital stays. Unanticipated extension of hospitalization stays can be a great burden not only to patients but to medical providers and insurance companies alike. MATERIALS AND METHODS: Data from 1096 patients who underwent one-level or two-level lumbar decompression AMS at an in-hospital, outpatient surgical facility between January 1, 2019, and March 16, 2020, were collected. Patients were categorized into three groups based on length of stay: (1) AMS, (2) OS, or (3) inpatient. Demographics, comorbidities, surgical information, and administrative information were collected. Simple and multivariable logistic regression analyses were conducted comparing AMS patients and OS/inpatient as well as OS and inpatients. RESULTS: Of the 1096 patients, 641 (58%) patients were converted to either OS (n=486) or inpatient (n=155). The multivariable analysis demonstrated that age (more than 80 yr old), high American Society of Anesthesiologists Physical Status (ASA) grade, history of sleep apnea, drain use, high estimated blood loss, long operation, late operation start time, and a high pain score were considered independent risk factors for AMS conversion to OS/inpatient. The risk factors for OS conversion to inpatient were an ASA class 3 or higher, coronary artery disease, diabetes mellitus, hypothyroidism, steroid use, drain use, dural tear, and laminectomy. CONCLUSIONS: Several surgical factors along with patient-specific factors were significantly associated with AMS conversion. Addressing modifiable surgical factors might reduce the AMS conversion rate and be beneficial to patients and facilities.

Association of healthy lifestyle and all-cause mortality according to medication burden.

BACKGROUND: Healthy lifestyle is associated with reduced all-cause mortality, but it is not known whether this association persists for individuals with high medication burden. We examined the association between healthy lifestyle behaviors and all-cause mortality across different degrees of polypharmacy. METHODS: This was a secondary analysis of 20,417 adults aged ≥45 years from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study. The primary exposure was healthy lifestyle (adherence to Mediterranean diet, physical activity, smoking abstinence, sedentary behavior avoidance, and composite healthy behavior score [HBS]). The primary outcome was all-cause mortality. Strata of medication burden were based on the number of medications taken (no polypharmacy: 0-4, polypharmacy: 5-9, hyperpolypharmacy: ≥10). We used Cox proportional hazards regression models to examine the association between healthy lifestyle behaviors and mortality within each medication burden stratum and examined for interactions with age. RESULTS: The healthiest category of each lifestyle behavior, except sedentary behavior avoidance among the hyperpolypharmacy group, was associated with lower all-cause mortality (hazard ratio [HR]) regardless of medication burden: Mediterranean diet (no polypharmacy: HR 0.77, polypharmacy: HR 0.78, hyperpolypharmacy: HR 0.85), physical activity (no polypharmacy: HR 0.87, polypharmacy: HR 0.82, hyperpolypharmacy: HR 0.79), smoking abstinence (no polypharmacy: HR 0.40, polypharmacy: HR 0.45, hyperpolypharmacy: HR 0.52), and sedentary behavior avoidance (no polypharmacy: HR 0.88, polypharmacy: HR 0.86, hyperpolypharmacy: HR 0.95). Higher HBS was inversely associated with all-cause mortality within each medication burden stratum (no polypharmacy: HR 0.52, polypharmacy: HR 0.55, hyperpolypharmacy: HR 0.69). Although there was an interaction with age among those with no polypharmacy and those with polypharmacy, point estimates for HBS followed a graded pattern whereby higher HBS was incrementally associated with improved mortality across all age strata. CONCLUSION: Greater adherence to a healthy lifestyle was associated with lower all-cause mortality irrespective of medication burden and age.

A multi-nutrient supplement reduced markers of inflammation and improved physical performance in active individuals of middle to older age: a randomized, double-blind, placebo-controlled study.

BACKGROUND: While exercise acts to combat inflammation and aging, the ability to exercise may itself be compromised by inflammation and inflammation's impact on muscle recovery and joint inflammation. A number of nutritional supplements have been shown to reduce inflammation and improve recovery. The purpose of the current investigation was to examine the effect of a multi-nutrient supplement containing branched chain amino acids, taurine, anti-inflammatory plant extracts, and B vitamins on inflammatory status, endothelial function, physical function, and mood in middle-aged individuals. METHODS: Thirty-one healthy and active men (N = 16, mean age 56 ± 6.0 yrs) and women (N = 15, mean age = 52 ± 7.5 yrs) participated in this investigation. Subjects completed one 28 day cycle of placebo supplementation and one 28 day cycle of multi-nutrient supplementation (separated by a one week washout period) in a balanced, randomized, double-blind, cross-over design. Subjects completed weekly perceptual logs (PROMIS-57, KOOS) and pre- and post- testing around the supplementation period. Testing consisted of brachial artery flow mediated dilation (FMD), blood measures, and physical performance on vertical jump, handgrip strength, and balance (dispersion from center of pressure). Significance for the investigation was p ≤ 0.05. RESULTS: IL-6 significantly decreased in both men (from 1.2 ± 0.2 to 0.7 ± 0.4 pg·mL(-1)) and women (from 1.16 ± 0.04 to 0.7 ± 0.4 pg·mL(-1)). Perceived energy also improved for both men (placebo: 1.8 ± 0.7; supplement: 3.7 ± 0.8 AUC) and women (placebo: 1.2 ± 0.7; supplement: 2.8 ± 0.8 AUC). Alpha-1-antichymotrypsin (from 108.9 ± 38.6 to 55.5 ± 22.2 ug·mL(-1)), Creatine Kinase (from 96 ± 34 to 67 ± 23 IU·L(-1)), general pain, and joint pain decreased in men only, while anxiety and balance (from 0.52 ± 0.13 to 0.45 ± 0.12 cm) improved in women only. Men showed increased performance in vertical jump power (from 2642 ± 244 to 3134 ± 282 W) and grip strength (from 42.1 ± 5.9 to 48.5 ± 4.9 kg). CONCLUSIONS: A multi-nutrient supplement is effective in improving inflammatory status in both men and women, markers of pain, joint pain, strength, and power in men only, and both anxiety and balance (a risk factor for hip fracture) in women. Therefore, a multi-nutrient supplement may help middle-aged individuals to prolong physical function and maintain a healthy, active lifestyle.

Effects of aging and Parkinson's disease on motor unit remodeling: influence of resistance exercise training.

Aging muscle atrophy is in part a neurodegenerative process revealed by denervation/reinnervation events leading to motor unit remodeling (i.e., myofiber type grouping). However, this process and its physiological relevance are poorly understood, as is the wide-ranging heterogeneity among aging humans. Here, we attempted to address 1) the relation between myofiber type grouping and molecular regulators of neuromuscular junction (NMJ) stability; 2) the impact of motor unit remodeling on recruitment during submaximal contractions; 3) the prevalence and impact of motor unit remodeling in Parkinson's disease (PD), an age-related neurodegenerative disease; and 4) the influence of resistance exercise training (RT) on regulators of motor unit remodeling. We compared type I myofiber grouping, molecular regulators of NMJ stability, and the relative motor unit activation (MUA) requirement during a submaximal sit-to-stand task among untrained but otherwise healthy young (YA; 26 yr, n = 27) and older (OA; 66 yr, n = 91) adults and OA with PD (PD; 67 yr, n = 19). We tested the effects of RT on these outcomes in OA and PD. PD displayed more motor unit remodeling, alterations in NMJ stability regulation, and a higher relative MUA requirement than OA, suggesting PD-specific effects. The molecular and physiological outcomes tracked with the severity of type I myofiber grouping. Together these findings suggest that age-related motor unit remodeling, manifested by type I myofiber grouping, 1) reduces MUA efficiency to meet submaximal contraction demand, 2) is associated with disruptions in NMJ stability, 3) is further impacted by PD, and 4) may be improved by RT in severe cases. NEW & NOTEWORTHY Because the physiological consequences of varying amounts of myofiber type grouping are unknown, the current study aims to characterize the molecular and physiological correlates of motor unit remodeling. Furthermore, because exercise training has demonstrated neuromuscular benefits in aged humans and improved innervation status and neuromuscular junction integrity in animals, we provide an exploratory analysis of the effects of high-intensity resistance training on markers of neuromuscular degeneration in both Parkinson's disease (PD) and age-matched older adults.

Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure.

Detyrosinated microtubules provide mechanical resistance that can impede the motion of contracting cardiomyocytes. However, the functional effects of microtubule detyrosination in heart failure or in human hearts have not previously been studied. Here, we utilize mass spectrometry and single-myocyte mechanical assays to characterize changes to the cardiomyocyte cytoskeleton and their functional consequences in human heart failure. Proteomic analysis of left ventricle tissue reveals a consistent upregulation and stabilization of intermediate filaments and microtubules in failing human hearts. As revealed by super-resolution imaging, failing cardiomyocytes are characterized by a dense, heavily detyrosinated microtubule network, which is associated with increased myocyte stiffness and impaired contractility. Pharmacological suppression of detyrosinated microtubules lowers the viscoelasticity of failing myocytes and restores 40-50% of lost contractile function; reduction of microtubule detyrosination using a genetic approach also softens cardiomyocytes and improves contractile kinetics. Together, these data demonstrate that a modified cytoskeletal network impedes contractile function in cardiomyocytes from failing human hearts and that targeting detyrosinated microtubules could represent a new inotropic strategy for improving cardiac function.

Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy.

PURPOSE: The myriad consequences of age-related muscle atrophy include reduced muscular strength, power, and mobility; increased risk of falls, disability, and metabolic disease; and compromised immune function. At its root, aging muscle atrophy results from a loss of myofibers and atrophy of the remaining type II myofibers. The purpose of this trial (NCT02442479) was to titrate the dose of resistance training (RT) in older adults in an effort to maximize muscle regrowth and gains in muscle function. METHODS: A randomized, four-arm efficacy trial in which four, distinct exercise prescriptions varying in intensity, frequency, and contraction mode/rate were evaluated: (1) high-resistance concentric-eccentric training (H) 3d/week (HHH); (2) H training 2d/week (HH); (3) 3d/week mixed model consisting of H training 2d/week separated by 1 bout of low-resistance, high-velocity, concentric only (L) training (HLH); and (4) 2d/week mixed model consisting of H training 1d/week and L training 1d/week (HL). Sixty-four randomized subjects (65.5±3.6y) completed the trial. All participants completed the same 4weeks of pre-training consisting of 3d/week followed by 30weeks of randomized RT. RESULTS: The HLH prescription maximized gains in thigh muscle mass (TMM, primary outcome) and total body lean mass. HLH also showed the greatest gains in knee extension maximum isometric strength, and reduced cardiorespiratory demand during steady-state walking. HHH was the only prescription that led to increased muscle expression of pro-inflammatory cytokine receptors and this was associated with a lesser gain in TMM and total body lean mass compared to HLH. The HL prescription induced minimal muscle regrowth and generally lesser gains in muscle performance vs. the other prescriptions. MAJOR CONCLUSIONS: The HLH prescription offers distinct advantages over the other doses, while the HL program is subpar. Although limited by a relatively small sample size, we conclude from this randomized dose-response trial that older adults benefit greatly from 2d/week high-intensity RT, and may further benefit from inserting an additional weekly bout of low-load, explosive RT. TRIAL REGISTRATION: ClinicalTrials.govNCT02442479.

Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson's disease.

We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2-3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations (P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45-56%, IV: +39-54%). These adaptations were accompanied by a host of functional and clinical improvements (P < 0.05): total body strength (+30-56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (-30%); 6-min walk (+43 m), Parkinson's Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (-5.7 pts) and motor (-2.7 pts); and fatigue severity (-17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON (P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.