Dr. Jacob A Siedlik

Age-related functional declines are thought to be caused by hallmark biological processes that manifest in physical, mental, and metabolic impairments compromising intrinsic capacity, healthspan and quality-of-life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in individual exercise responsiveness. This inter-individual response heterogeneity (IRH) was first extensively interrogated by Bouchard and colleagues in the context of endurance training. Our group has interrogated IRH in response to resistance training and combined training, and we have conducted trials in older adults examining dose titration and adjuvant treatments in attempts to boost response rates. Despite the work of many groups, the mechanisms underpinning IRH and effective mitigation strategies largely remain elusive. The National Institute on Aging (NIA) hosted a focused workshop in 2022 titled "Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in old adults". This workshop spurred a dedicated NIA request for applications (RFA) with the major goal "to better understand factors underlying response variability to exercise training in older adults." We developed a two-phase Sequential Multiple Assignment Randomized Trial (SMART) in response to the RFA that will allow us to classify individual responsiveness to combined endurance and resistance training and interrogate potential mechanistic underpinnings (Phase I), followed by an approach to boost responsiveness (Phase II). Using deep in vivo, ex vivo, and molecular phenotyping, we will establish multidimensional biocircuitry of responsiveness and build predictive models, providing a basis for personalized exercise prescriptions.

Background:
Resistance training with real-time movement velocity feedback enhances power training. Linear position transducers (LPTs) provide visual biofeedback and are commonly used to measure movement velocities in performance and research settings. However, the agreement between some commonly used LPTs, such as the Humac360, is unknown.

Objective:
The purpose of this study was to determine the agreement of the Humac360 LPT between the Tendo Power Analyzer and the GymAware PowerTool.

Methods:
Thirty participants (23.0 ± 5.6 years) completed 7 sets of 3 repetitions of the belt squat movement with loads ranging from 0–120% of their body weight. Mean velocity (MV) and peak velocity (PV) were collected and recorded simultaneously on all three LPTs. Agreement between devices was assessed using the ratio of half the limits of agreement and the mean of pairwise measurements, and the correlation between devices was determined using Pearson's r.

Results:
Moderate agreement was seen at PV between the Humac360 and Tendo (0.5 LOA/MPM = 0.12–0.21), and between the Humac360 and GymAware (0.5 LOA/MPM = 0.16–0.27). Low agreement was observed when measuring MV between the Humac360 and Tendo (0.5 LOA/MPM = 0.23–0.31), and between the Humac360 and GymAware (0.5 LOA/MPM = 0.18–0.27). High to very high correlations were observed between the Humac360 and both the Tendo (r = 0.87–0.99) and GymAware (r = 0.87–0.96) at MV and PV.

Conclusion:
The moderate agreement and high to very high positive correlations demonstrated by the Humac360 was comparable to the Tendo and GymAware devices, specifically at peak velocities, supporting its use by clinicians, therapists, and trainers, for the particular use of measuring peak velocity.

Conventional belief is that high-intensity (HI) exercise inhibits immune function; however, recent work challenges this position. The purpose of this was to quantify changes in T cell proliferative capacity following either a HI or moderate-intensity (MI) exercise. Sixteen males were randomly selected to a HI or MI exercise group. Blood was obtained baseline and immediately, 1-, 4-, and 6-hours post-exercise for analyses of CD3+ T cell proliferation (co-stimulation via PHA or CD3+CD28). The proliferative response increased in T cells in the HI group and remained significantly elevated up to 6-hours post-exercise in both co-stimulation conditions. In contrast, the MI group saw no change proliferative ability following exercise. Analyses of serum stress hormones, and immunomodulatory cytokines failed to reveal any correlated variations that could clarify the T cell findings. We suggest the increase in proliferative capacity following HI exercise is indicative of an exercise-induced activation that provides for enhanced functional responses to stimuli. Moreover, this study shows that HI exercise increases T cell processes, effectively priming them for activation in response to stimuli. This study is registered with ClinicalTrials.gov (NCT06638684).

A momentous amount of health data has been and is being collected. Across all levels of health care, data are driving decision-making and impacting patient care. A new field of knowledge and role for those in health care is emerging—the need for a health data–informed workforce. In this viewpoint, we describe the approaches needed to build a health data–informed workforce, a new and critical skill for the health care ecosystem.

This study investigated the effect of a commercially available ketone supplement on heart rate (HR), perceived exertion (RPE), blood lactate, glucose, and ketone concentrations, along with time to fatigue (TTF) during a running task to voluntary fatigue. Twelve NCAA Division I cross-country athletes took part in this randomized, double-blind, placebo-controlled cross-over study. Bayesian methodologies were employed for all statistical analyses, and point estimates were determined to be statistically significant if the 95% highest-density intervals (HDI) excluded zero. TTF was not significantly different between conditions with a Meandiff = 48.7 ± 6.3 s (95% HDI: −335, 424) and a 0.39 probability derived from the posterior distribution, indicating the likelihood that the supplement would increase TTF compared to the placebo control. Lactate concentrations immediately post-exercise were significantly lower in the supplement trial relative to placebo with an estimated Meandiff = −4.6 ± 1.9 mmol; 95% HDI: −8.3, −0.9. There were no significant interaction effects observed for either blood glucose or ketone concentrations nor HR or RPE. These findings imply that the acute ingestion of ketones before running at lactate threshold pace has a low probability of increasing TTF in highly trained Division I runners.

The purpose of this study was to determine the effect of a multicomponent rehabilitation protocol on functional outcomes in a post-acute care facility.
Eleven older, medically complex patients (80.3 ± 7.3 yrs) completed a multicomponent rehabilitation protocol during a stay at a post-acute care facility. Gait speed, Berg Balance scores, and sit-to-stand velocity were examined upon admission and discharge. Bayesian paired sample t-tests were used to determine changes from PRE to POST and linear regression analyses were used to determine the influence of length of stay.
Gait speed increased by 0.26 m/s (49% increase) from PRE (0.65 ± 0.38 m/s) to POST (0.90 ± 0.42 m/s) exercise intervention (p = 0.013). Berg Balance Scores significantly increased by 26% from PRE (38.27 ± 8.33) to POST (45.73 ± 3.32) exercise intervention (p = 0.009). A 45% increase in STS velocity from PRE (0.37 ± 0.14 m/s) to POST (0.51 ± 0.13 m/s; p ≤ 0.001) was observed following the multicomponent rehabilitation protocol. Length of stay did not influence improvements in gait speed, Berg Balance Scores, nor Sit-to-stand velocity (p = 0.176-0.811).
The multicomponent rehabilitation protocol with movement velocity biofeedback is feasible in a post-acute care facility in medically complex older patients and demonstrates improvements in clinical mobility and balance outcomes.

Gastrointestinal (GI) disturbances are a prevalent cause of marathon related complaints, and in extreme cases can promote life-threatening conditions such as exertional heat stroke. Our aim was to study intestinal cell injury [via intestinal fatty acid binding protein (I-FABP)] and perceived GI distress symptoms among marathon runners. We also examined potential risk factors (e.g., inadequate sleep) that could exacerbate GI disturbances in healthy, trained endurance runners. This was a parallel mixed-methods study design. 2019 Boston Marathon participants were recruited via email and subjects completed surveys before the race describing demographics and training history. Participants completed a GI questionnaire to assess presence and severity of symptoms, a survey regarding risk factors (e.g., recent illness, medications) that could promote GI disturbances, and provided a urine sample at three time points (immediately pre-race, post-race, and 24-h post-race). Due to weather, blood samples were only collected immediately and 24-h post-race. A total of 40 runners (males: n = 19, age = 44.9 ± 10.8 years; females: n = 21, age = 44.8 ± 10.6 years) completed this study. I-FABP significantly decreased from post-race (3367.5 ± 2633.5 pg/mL) to 24-h post-race (1657.3 ± 950.7 pg/mL, t (39) = −4.228, p< .001, d = −.669). There was a significant difference in overall GI symptom scores across the three time points
(F (2, 39) = 41.37,p< .001). The highest average score occurred post-race (.84 ± .68), compared to pre-race (.09 ± .12) and 24-h post-race (.44 ± .28). Post-race I-FABP (r = .31,p= .048) and post-race urine specific gravity (r = .33,p= .041) were significantly correlated with post-race GI symptom scores. Our study provides further support to the individualized nature of GI disturbances, with participants experiencing a wide range of risk factors that can influence the extent of GI damage and perceived symptoms during and after exercise.

Doxorubicin (DOX), a potent chemotherapy agent, useful in the treatment of solid tumors, lymphomas, and leukemias, is limited by its potentially lethal cardiotoxicity. However, exercise has been consistently shown to mitigate the side effects of DOX, including cardiotoxicity. To date, most studies examining the relationship between exercise and DOX-induced cardiotoxicity have focused on aerobic exercise, with very few examining the role of anerobic activity. Therefore, this investigation explored the potential of creatine (CR) and resistance training (RT) in preserving cardiac health during DOX therapy. Male Sprague-Dawley rats were grouped into RT, RT + CR, sedentary (SED), and SED + CR, with each division further branching into saline (SAL) or DOX-treated subsets post-10 weeks of RT or SED activity. RT comprised progressive training utilizing specialized cages for bipedal stance feeding. CR-treated groups ingested water mixed with 1% CR monohydrate and 5% dextrose, while control animals received 5% dextrose. At week 10, DOX was administered (2 mg/kg/week) over 4-weeks to an 8 mg/kg cumulative dose. Cardiac function post-DOX treatment was assessed via transthoracic echocardiography. Left ventricular diameter during diastole was lower in DOX + CR, RT + DOX, and RT + CR + DOX compared to SED + DOX (p < 0.05). Additionally, cardiac mass was significantly greater in RT + CR + DOX SED + DOX animals (p < 0.05). These results suggest RT and CR supplementation, separately and in combination, could attenuate some measures of DOX-induced cardiotoxicity and may offer a cost-effective way to complement cancer treatments and enhance patient outcomes. More investigations are essential to better understand CR's prolonged effects during DOX therapy and its clinical implications.

Traumatic spinal cord injury (SCI) results in wide-ranging cellular and systemic dysfunction in the acute and chronic time frames after the injury. Chronic SCI has well-described secondary medical consequences while acute SCI has unique metabolic challenges as a result of physical trauma, in-patient recovery and other post-operative outcomes. Here, we used high resolution mass spectrometry approaches to describe the circulating lipidomic and metabolomic signatures using blood serum from mice 7 d after a complete SCI. Additionally, we probed whether the aporphine alkaloid, boldine, was able to prevent SCI-induced changes observed using these 'omics platforms'. We found that SCI resulted in large-scale changes to the circulating lipidome but minimal changes in the metabolome, with boldine able to reverse or attenuate SCI-induced changes in the abundance of 50 lipids. Multiomic integration using xMWAS demonstrated unique network structures and community memberships across the groups.

Pearson, JR, Moodie, N, Stout, KW, Hawkins, WC, Matuszek, M, Graham, ZA, Siedlik, JA, Vardiman, JP, and Gallagher, PM. Similar responses in the Akt/protein kinase B (PKB) signaling pathway after different lower-body exercise volumes in recreationally active men. J Strength Cond Res 37(5): 1034-1041, 2023-This project examined the differences between a single set (SS) compared to multiple sets (MS) of resistance exercise on the Akt/protein kinase B (PKB) signaling pathway, the expression of insulin-like growth factor-1 (IGF-1), and the receptor for IGF-1 (IGF-1R) to better understand the types of resistance training protocols that are most beneficial in stimulating the muscle hypertrophic response. Sixteen healthy men were randomly selected into 2 groups of 8. Subjects in each group received 3 biopsies: (a) before exercise, (b) 15 minutes postexercise, and (c) 180 minutes postexercise. Subjects in the SS group performed 1 set of leg press to failure at 80% of their predetermined 1 repetition maximum (1RM). Subjects in the MS group performed 2 sets of 10 repetitions and 1 set to failure at 80% of their predetermined 1RM, with 3 minutes of rest between each set. Our results indicated no group x time interactions in the concentration of Akt signaling proteins. Furthermore, there were no group x time interactions in IGF-1 or IGF-1R expression. However, phosphorylated 4E-binding protein 1 levels increased 150% from pre to 180 minutes post (p = 0.005). In addition, there was a significantly greater increase in IGF-1R expression in the SS group compared with the MS group (7.99 +/- 10.07 vs. 4.41 +/- 6.28; p = 0.026). Collectively, we found that a SS of resistance training evokes a similar acute Akt/PKB pathway response as MS in recreationally active men.