Resistance Training and Muscle-Brain Crosstalk: Implications for Cognitive Decline in Aging and Spinal Cord Injury

Resistance exercise is an efficacious stimulus for improving cognitive function in older adults, which may be mediated by the upregulation of blood-borne neurotrophic growth factors (NTFs) like brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). However, the NTF response to resistance exercise and training in older adults is poorly understood. Therefore, the purpose of this study was to characterize the timing and magnitude of the NTF response following an acute bout of resistance exercise before and after 8 weeks of resistance training. Ten cognitively normal, older adults (ages 60-77 years, five men) were examined. The acute NTF response to resistance exercise was assessed via serum samples drawn at designated time points following exercise. This procedure was then repeated following 8 weeks of resistance training. BDNF increased immediately post-exercise (Δ9% pre-training, Δ11% post-training) then returned to resting levels while IGF-1 remained stable following resistance exercise before and after 8 weeks of resistance training. Basal levels of both NTFs were unaffected by the 8 week training period. We report a transient increase in serum BDNF following a bout of resistance exercise in older adults, which could have implications for the design of interventions seeking to maximize cognitive function in older adults.

The loss of skeletal muscle mass and strength during aging, sarcopenia, increases the risk for falls and dependency. Resistance exercise (RE) training is effective at improving muscle mass and strength in older adults; however, aging is associated with reduced training-induced hypertrophy. Recent research has illustrated an impaired muscle protein synthetic response following an acute bout of RE in older adults but much less is known regarding the effect of acute RE on muscle protein breakdown (MPB). We hypothesize that the ubiquitin proteasome system and the autophagosomal-lysosomal system may regulate the overall rate of MPB during postexercise recovery. Muscle biopsies of the vastus lateralis were sampled from 16 older (age = 70±2 years) and 16 younger (age = 27±2 years) participants at baseline and at 3, 6, and 24 hours following an acute bout of RE. In conjunction with stable isotopic techniques to measure MPB, we utilized immunoblotting and RT-PCR to examine protein and mRNA expression for key signaling molecules in both the ubiquitin proteasome system and the autophagosomal-lysosomal system. MuRF1 mRNA expression increased, whereas GABARAP mRNA decreased after RE in both younger and older adults (p < .05). The LC3B-II/LC3B-I protein ratio decreased in both groups after RE (p < .05), but MPB was not different 24 hour post-RE in either group (p > .05). Aging does not influence skeletal MPB, autophagy, or the ubiquitin proteasome system following an acute bout of RE. Therefore, targeting the muscle protein synthesis response to exercise may hold more promise in the prevention of sarcopenia.

P1. Improvement of motor function induced by skeletal muscle contraction in spinal cord injury rats

BackgroundPersons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities.Methods/DesignForty-eight persons aged 18–65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function.DiscussionTraining through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks.Trial registrationClinicalTrials.gov, NCT02660073. Registered on 21 Jan 2016.

Aging is associated with negative changes in autonomic function and an increased risk of cardiovascular disease. The risk of a sudden cardiovascular event is elevated during and immediately following vigorous exercise, potentially due to increased sympathetic dominance. Because resistance exercise provides a large hypertensive stimulus and young adults show reduced cardiac vagal control during recovery, further exploration of the effects of an acute bout of resistance exercise on autonomic function and recovery in older adults is required.PurposeTo evaluate the effects of high‐intensity lower body resistance exercise on autonomic modulation in young (YA) and older adults (OA).MethodsThirty‐five YA (17 female, 26±5 years, BMI: 23.8±3.2 kg/m2) and 25 OA (14 female, 60±6 years, BMI: 29.9±5.4 kg/m2) completed 3 sets of 10 repetitions of maximal isokinetic knee flexion/extension on a force dynamometer in a semi‐recumbent position. Throughout the protocol, participants were instrumented with a 3‐lead ECG and finger‐photoplethysmography for continuous heart rate and blood pressure recordings. Time and spectral components of heart rate (HRV) and blood pressure variability (BPV), non‐invasive indices of autonomic function, were analyzed using five‐minute segments at baseline and 5‐minutes post‐resistance exercise.ResultsAt baseline, OA had higher systolic and mean blood pressure, as well as lower root mean square of successive differences (RMSSD), low‐frequency (LF) RRI, high‐frequency (HF) RRI, and baroreceptor sensitivity (BRS) (p&lt;0.05). At 5‐minutes post‐exercise, LF/HF ratio and LF systolic blood pressure increased (p&lt;0.05). RMSSD, HF RRI, and BRS, were greater at baseline for YA and all variables decreased at 5‐min, while older adults did not change over time (interactions, p&lt;0.05).ConclusionsThese results suggest YA exhibited parasympathetic withdrawal 5‐minutes post‐exercise, whereas OA either did not exhibit parasympathetic withdrawal or had already recovered at 5 min post exercise, but this cannot be distinguished from our data. Both groups appear to have elevated sympathetic modulation at 5‐min, as indicated by RRI, LF/HF and LF BPV. Further investigation of the response during exercise is required. However, there are clear differences in autonomic recovery following maximal resistance exercise in OA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparative efficacy of exercise interventions for cognitive health in older adults: A network meta-analysis.

Several recent studies have noted a blunted muscle protein synthetic response following an acute bout of resistance exercise (RE) in older individuals. Much less is known regarding the effect of age on the muscle protein breakdown response to RE. The effect of age on the regulation of muscle anabolic and catabolic signaling pathways following RE is not well characterized. We hypothesized that aging would be associated with a reduced overall muscle protein anabolic response. PURPOSE: To determine whether a differential aging response exists in skeletal muscle protein synthesis and breakdown signaling during a 24h time-course following a bout of RE. METHODS: 8 young (age=27±2 yrs) and 8 older subjects (age=70±2 yrs) performed a bout of leg-extensions at 70% 1RM. Muscle biopsies were obtained from the vastus lateralis at baseline and at 3, 6 and 24h post-exercise. Intracellular signaling was assessed with immunoblotting methods. RESULTS: We observed a significant increase in the phosphorylation of S6K1 (Thr389) (0.14+0.02 vs 0.26+0.02 AU) and rpS6 (Ser240/244) (0.04+0.0 vs 0.07+0.0) at all post-exercise time points in the young (P<0.05), with no changes in the older subjects (0.14+.01 vs 0.13+.01, S6K1) (0.05+0.0 vs 0.05+0.0, rpS6) (P>0.05). Older subjects also had a reduced S6K1/rpS6 phosphorylation compared to the young at 6 and 24h post-exercise (P<0.05). Our preliminary data for catabolic signaling shows that phospho-Akt (Thr308), an upstream effector of E3 ubiquitin ligases, increased at 3 and 6h post-exercise in the young (P<0.05) with no changes in the older subjects (P>0.05). Akt phosphorylation was also higher in young compared to old at 6 and 24h post-exercise (P<0.05). Total LC3B protein, indicative of autophagy induction, decreased at both 6 and 24h post-exercise in the young subjects (1.07+0.13 vs 0.59+0.06) (P<0.05) and decreased at all post-exercise time points in the old (1.09+0.12 vs 0.60+0.09) (P<0.05). CONCLUSIONS: We conclude that aging is associated with a dysregulation of anabolic and catabolic signaling following RE which may contribute to the blunted muscle protein anabolic response to RE in older adults. Supported by NIH/NIAMS R01AR049877, P30AG024832 and T32HD07539.

Introduction: Individuals with spinal cord injuries (SCI) exhibit an accelerated age-related cognitive decline compared to healthy individuals, even after adjusting for mood factors and concomitant traumatic brain injury. We hypothesized that neuromuscular electrical stimulation (NMES) on hamstring and gluteal muscles may induce a dose-dependent increase in lactate and insulin-like growth factor-1 (IGF-1) which is hypothesized to be associated with a temporary enhancement of cognitive performance. Methods: Twenty-two individuals with chronic SCI participated in a randomized cross-over study, receiving NMES on one of both visits. Participants randomly underwent a single session of 30 or 60-minute NMES. Lactate, IGF-1 levels and processing speed on the Symbol Digit Modalities test (SDMT) were tested before, immediately after and 30 minutes after intervention or 60 minutes rest. Results: Lactate levels increased significantly immediately after NMES conditions compared to control (p = 0.004). Lactate increases were larger in the 30-minute NMES group compared to the 60-minute NMES group, consistent with the higher current amplitude applied in the former (100 mA compared to 40 mA). IGF-1 increases did not significantly differ between groups (p = 0.262), and there were no significant differences in SDMT performance changes over time between groups (p = 0.892). Conclusion: Acute NMES did not induce changes in IGF-1 levels or cognitive performance in individuals with SCI. However, 30 min of 100 mA of NMES significantly increased lactate levels, and could be used as a marker of NMES intensity in this population. Further research is required to explore various NMES protocols and their impact on cognitive domains in individuals with SCI.

BackgroundWith the increase in life expectancy, age-related cognitive decline has become a prevalent concern. Physical activity (PA) is increasingly being recognized as a vital non-pharmacological strategy to counteract this decline. This review aimed to (i) critically evaluate and synthesize the impact of different PA and exercise modalities (aerobic, resistance, and concurrent training) on cognitive health and overall well-being in older adults, (ii) discuss the influence of exercise intensity on cognitive functions, and (iii) elucidate the potential mechanisms through which PA and exercise may enhance or mitigate cognitive performance among older adults.Main BodyAn exhaustive analysis of peer-reviewed studies pertaining to PA/exercise and cognitive health in older adults from January 1970 to February 2025 was conducted using PubMed, Scopus, Web of Science, PsycINFO, and MEDLINE. There is compelling evidence that aerobic and resistance training (RT) improve cognitive function and mental health in older adults, with benefits influenced by the type and intensity of exercise. Specifically, moderate-intensity aerobic exercise appears to bolster memory, executive functions, and mood regulation, potentially through increased cerebral blood flow, neurogenesis, and production of brain-derived neurotrophic factors in the hippocampus. Moderate-to-high-intensity RT acutely enhances visuospatial processing and executive functions, with chronic training promoting neurogenesis, possibly by stimulating insulin-like growth factor-1 and augmenting blood flow to the prefrontal cortex. Findings related to the effects of concurrent training on cognitive function and mental health are heterogeneous, with some studies reporting no significant impact and others revealing substantial improvements. However, emerging evidence indicates that the combination of concurrent training and cognitive tasks (i.e., dual tasks) is particularly effective, often outperforming aerobic exercise alone.ConclusionsRegular aerobic and RT performance is beneficial for older adults to mitigate cognitive decline and enhance their overall well-being. Specifically, engaging in moderate-intensity aerobic exercises and moderate-to-high-intensity RT is safe and effective in improving cognitive function and mental health in this demographic. These exercises, which can be conveniently incorporated into daily routines, effectively enhance mental agility, memory, executive function, and mood. The findings related to concurrent training are mixed, with emerging evidence indicating the effectiveness of combined concurrent and cognitive tasks on cognitive health and well-being in older adults.Key Points- Moderate-intensity aerobic exercise is associated with significant improvements in cognitive function, mood regulation, and overall well-being in older adults. These benefits are linked to structural and functional changes in the brain such as increased hippocampal volume and elevated levels of brain-derived neurotrophic factor.- Moderate-to-high-intensity resistance training, both in acute and chronic forms, enhances cognitive performance in older adults, particularly in executive functions and visuospatial processing. Cognitive benefits, including improvements in information-processing speed, attention, and memory, can be sustained through regular training.- The effects of concurrent resistance and aerobic training on cognitive function in older adults are mixed. However, combining concurrent training with cognitive tasks (i.e., dual-task training) is particularly effective and often outperforms aerobic exercise alone.- Cognitive and well-being improvements from aerobic and resistance training are mediated by mechanisms such as increased cerebral blood flow and oxygen delivery, enhanced neurogenesis, reduced oxidative stress and inflammation, and positive hormonal changes.- While the optimal exercise dosage for promoting cognitive health in older adults remains undetermined, empirical evidence indicates a positive correlation between increased exercise dosage and cognitive health improvements.

Skeletal muscle atrophy, decreased fat-free mass (FFM) and increased fat mass (FM) are common adaptations in individuals with spinal cord injury (SCI). Evoked resistance training (RT) using neuromuscular electrical stimulation (NMES) and ankle weights to the paralyzed skeletal muscles has been shown to evoke significant hypertrophy. PURPOSE: To determine the effects of 12 weeks of NMES RT and diet when compared to diet only on skeletal muscle cross-sectional area (CSA), subcutaneous adipose tissue (SAT) CSA and body composition (FFM and FM). METHODS: Nine individuals with motor complete SCI (C5-T11, 35 ± 9 years, 22 ± 4 kg/m2) were randomly assigned into one of two groups; RT + diet (n= 5) or diet control (n=4). The RT+ diet underwent 12weeks of progressive RT of the right and left knee extensors muscle groups using NMES and ankle weights. Weekly feedback was provided to both groups to maintain a standard diet at 45% carbohydrate, 30% fat and 25% protein. T1 weighted magnetic resonance images of both thighs and whole body dual x-ray absorptiometry were acquired prior to and after training. Analysis of covariance was used to test for statistical difference. RESULTS: Prior to training, skeletal muscle CSAs of the whole thigh, knee extensors and knee flexors were not different in the RT + diet versus diet. Following training, skeletal muscle hypertrophy was detected in the whole thigh (77.5 ± 16 vs. 53 ± 26 cm2, P < 0.0001), knee extensors (35 ± 3 vs. 26 ± 13 cm2, P < 0.0001) and knee flexors (22 ± 8 vs. 16 ± 6 cm2, P < 0.0001) in the RT + diet group versus the diet group, respectively. The RT + diet group skeletal muscle CSA of the whole thigh, knee extensors and knee flexors increased by 28%, 35% and 16%, P < 0.0001, respectively; while no change was observed in the diet group. There were no significant changes in the thigh SAT or whole body composition in either group. CONCLUSION: Twice a week of Evoked RT to the paralyzed lower extremities resulted in significant skeletal muscle hypertrophy in individuals with SCI. However, the length of training was not sufficient to induce changes in whole body composition or SAT. Supported by Research Support Fund Grant from Indiana University

Validity of repetitions in reserve for prescribing resistance exercise in older adults.

Intramyocellular lipid (IMCL) is an important energy substrate during physical activity for young as well as older adults. However age-related changes in lipid metabolism can cause excess IMCL accumulation that can induce insulin resistance. Our previous studies have reported that IMCL content is inversely correlated with physical activity level in young, while it is not in the older adults (Hioki et al. 2018). In contrast, electromyostimulation (EMS) has been used to improve muscle mass, strength, and metabolism after spinal cord injury or chronic heart failure. PURPOSE: We aimed to prove the hypothesis that EMS can induce changes in the IMCL content of the vastus lateralis (VL) in older adults. METHODS: Fourteen physically active, non-obese older men and women were randomly assigned to an EMS group (70.4 ± 1.8 years) or a control group (without EMS) (68.0 ± 1.4 years) (n = 7 each). We applied EMS to the VL of the right leg for 30 min at a frequency of 30 Hz, pulse duration 300 μs, and contraction/relaxation durations of seven seconds on and seven seconds off. IMCL content in the VL was quantified by 1H-magnetic resonance spectroscopy before and immediately after the EMS in the EMS group, as well as in the control group. 1H-MRS spectra with and without water suppression were taken, and calculation of IMCL contents and creatine (Cr) (mM) was performed by the LCModel software. Fasting plasma glucose and insulin values were also determined from blood samples collected before and immediately after EMS. RESULTS: In the EMS group, values for IMCL/Cr increased significantly from 4.8 ± 2.1 to 6.9 ± 2.5 (p < 0.05) and plasma glucose decreased significantly from 96.4 ± 4.0 to 93.0 ± 3.4 mg/dL (p < 0.05); whereas, insulin did not change significantly (5.6 ± 1.1 vs. 5.2 ± 1.2 μIU/mL; p = 0.43). Values for IMCL/Cr did not change significantly after resting for 30 min in the control group (4.9 ± 2.1 vs. 5.0 ± 1.1, p = 0.95). Creatine values did not change after EMS in the EMS group (63.3 ± 3.4 vs. 62.9 ± 8.4 mM, p = 0.96) or after resting in the control group (63.3 ± 7.4 vs. 65.6 ± 8.9 mM, p = 0.76). CONCLUSION: The findings suggested that a single bout of EMS induces an increase in the IMCL content in the VL of older adults. This study was supported by a Grant in Aid (KAKENHI No. 23650432) and the Descente and Ishimoto Memorial Foundation for the Promotion of Sports Science.

Resistance training (RT) evokes skeletal muscle hypertrophy via increasing insulin growth factors-1 (IGF-1) after spinal cord injury (SCI). Muscle hypertrophy increases basal metabolic rate (BMR) following 16 weeks of RT; increase in BMR is also linked positively to adiponectin after SCI. The effects of combining testosterone replacement therapy (TRT) and RT on circulating growth factors, adiponectin and inflammatory biomarkers are still unclear. PURPOSE: To examine the effects of TRT+RT on IGF-1, insulin growth factors binding protein-3 (IGFBP-3), adiponectin and interlukin-6 (IL-6) compared to TRT only in men with SCI. METHODS: Twenty-two men with motor complete SCI were randomized into either 16 weeks of TRT+RT (n = 11) or TRT (n = 11). After overnight fast, IGF-1, IGFBP-3, adiponectin and IL-6 were measured. Evoked progressive RT using neuromuscular electrical stimulation (2 lbs. increments) was administered twice weekly. Daily TRT patches (2-6 mg/day) were applied on both shoulders at bedtime for 16 weeks. RESULTS: IGF-1 showed a decrease (P=0.008) in both TRT+RT (n=11; B2: 169.5±96.5 to PI: 101.5±28 ng/ml) and TRT only (n=11; B2: 136±74 to PI: 99±36 ng/ml) groups. IGFBP-3 increased significantly (P=0.0001) in both TRT+RT (n=11; B2: 1764±665 to PI: 2548.5±853 ng/ml) and TRT (n=11; B2: 1918.5±587 to PI: 2778±967 ng/ml). A significant interaction was noted between TRT+RT and TRT groups in the circulating adiponectin (P=0.024). IL-6 decreased (P=0.039) in TRT+RT (n=8; B2:5.5±5.6 to PI: 2.9±5.4 pg/ml) and TRT (n=10; B2:5.9±6.0 to PI: 3.9±4.4 pg/ml) groups. CONCLUSION: Greater adipose tissue in men with SCI may have resulted in aromatization of testosterone to estradiol that has been previously shown to decrease IGF-1 and increase IGFBP-3. Increased circulating testosterone following TRT+RT may be responsible for suppressing adiponectin but not in the TRT group. Finally, administering TRT with or without RT may elicit anti-inflammatory effects after SCI.

BackgroundWhile aerobic, resistance, and balance training are commonly used to counteract age-related declines in cognitive and physical functions, evidence for cognitive benefits of metabolic training (i.e., aerobic, resistance) remains inconsistent. In contrast, motor training (i.e., balance, coordination) involving higher task complexity may enhance cognition by engaging brain regions associated with cognitive control processes. Resistance training on unstable devices, also referred to as metastable resistance training (MRT), has been reported to increase metabolic, coordinative, and cognitive demands during exercise, as well as to improve cognitive performance in older adults. This study examined the effect of MRT on cognitive performance compared to traditionally recommended resistance training (T-RT) and balance training (BT). We hypothesized that MRT specifically improves cognitive task performance requiring perceptual processing and attention.MethodsEighty-three healthy older adults (mean age 70.5 ± 4.5 years) were matched into three groups which were randomly assigned to either MRT, BT or T-RT programs. Each group trained twice a week for 10 weeks. Cognitive functions were assessed using four tasks targeting working memory, inhibitory control, cognitive flexibility, and perceptual processing. Linear mixed-effects models were applied to examine the effect of MRT on cognitive performance in contrast to BT and T-RT.ResultsA significant time-by-group interaction was observed for inhibitory control when contrasting MRT with BT, t(80) = 3.56, p < 0.001, β = 0.42, 95% CI [0.19, 0.65], indicating improved response inhibition following MRT. Additionally, perceptual processing was significantly enhanced when comparing MRT with BT for both reaction time, t(79) = 2.35, p = 0.020, β = 0.19, 95% CI [0.03, 0.35], and accuracy, t(79) = -2.69, p = 0.009, β = -0.26, 95% CI [-0.45, -0.07].ConclusionsIn contrast to BT, MRT appears to selectively enhance cognitive functions requiring inhibitory control and perceptual processing in older adults. Consequently, metabolic demands associated with MRT may offer additional cognitive benefits beyond the coordinative demands offered by traditional balance training.Clinical trial numberThis trial, DRKS00030394, was registered in the German Clinical Trials Register on 16/08/2023.

IntroductionResistance exercise has been shown to improve muscle health in older adults and is recommended as a front-line treatment for many health conditions, including sarcopenia and frailty. However, despite considerable...