Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.

BACKGROUND: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity. METHODS: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex). RESULTS: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance. CONCLUSIONS: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.

Phosphorylations and Acetylations of Cytochrome c Control Mitochondrial Respiration, Mitochondrial Membrane Potential, Energy, ROS, and Apoptosis.

Cytochrome c (Cytc) has both life-sustaining and cellular death-related functions, depending on subcellular localization. Within mitochondria, Cytc acts as a single electron carrier as part of the electron transport chain (ETC). When released into the cytosol after cellular insult, Cytc triggers the assembly of the apoptosome, committing the cell to intrinsic apoptosis. Due to these dual natures, Cytc requires strong regulation by the cell, including post-translational modifications, such as phosphorylation and acetylation. Six phosphorylation sites and three acetylation sites have been detected on Cytc in vivo. Phosphorylations at T28, S47, Y48, T49, T58, and Y97 tend to be present under basal conditions in a tissue-specific manner. In contrast, the acetylations at K8, K39, and K53 tend to be present in specific pathophysiological conditions. All of the phosphorylation sites and two of the three acetylation sites partially inhibit respiration, which we propose serves to maintain an optimal, intermediate mitochondrial membrane potential (ΔΨm) to minimize reactive oxygen species (ROS) production. Cytc phosphorylations are lost during ischemia, which drives ETC hyperactivity and ΔΨm hyperpolarization, resulting in exponential ROS production thus causing reperfusion injury following ischemia. One of the acetylation sites, K39, shows a unique behavior in that it is gained during ischemia, stimulating respiration while blocking apoptosis, demonstrating that skeletal muscle, which is particularly resilient to ischemia-reperfusion injury compared to other organs, possesses a different metabolic strategy to handle ischemic stress. The regulation of Cytc by these post-translational modifications underscores the importance of Cytc for the ETC, ΔΨm, ROS production, apoptosis, and the cell as a whole.

The Influence of Cold Therapy on the Physical Working Capacity at the Electromyographic Threshold for Consecutive Exercise Sessions.

BACKGROUND: The purpose of this study was to determine whether cold therapy after the first exercise test influences the physical working capacity at the fatigue threshold (PWCFT) during the second exercise test. We hypothesized that cold therapy would delay the onset of PWCFT for the second exercise test relative to the control visit (i.e., no cold therapy). METHODS: Eight healthy college-aged men volunteered for the present study. For each of the two visits, subjects performed incremental, single-leg, knee-extensor ergometer, followed by either resting for 30 min (control visit) or having a cold pack applied for 15 min and then resting for 15 min (experimental visit). Then, the same exercise test was performed. The order of visits (control vs. experimental) was randomized for each subject. The exercise indices and PWCFT were determined for each of the two visits and statistically analyzed using two-way repeated measures analysis of variance. RESULTS: The results indicate no significant (p > 0.05) mean differences for maximal power output, heart rate at end-exercise, and PWCFT between the control and cold therapy visits. Moreover, there were no significant (p > 0.05) mean differences between the first and second exercise workbout within each visit. CONCLUSIONS: The findings of this study suggest that cold therapy did not influence neuromuscular fatigue.

Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle.

Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.

Non-invasive treatment of ischemia/reperfusion injury: Effective transmission of therapeutic near-infrared light into the human brain through soft skin-conforming silicone waveguides.

Noninvasive delivery of near-infrared light (IRL) to human tissues has been researched as a treatment for several acute and chronic disease conditions. We recently showed that use of specific IRL wavelengths, which inhibit the mitochondrial enzyme cytochrome c oxidase (COX), leads to robust neuroprotection in animal models of focal and global brain ischemia/reperfusion injury. These life-threatening conditions can be caused by an ischemic stroke or cardiac arrest, respectively, two leading causes of death. To translate IRL therapy into the clinic an effective technology must be developed that allows efficient delivery of IRL to the brain while addressing potential safety concerns. Here, we introduce IRL delivery waveguides (IDWs) which meet these demands. We employ a low-durometer silicone that comfortably conforms to the shape of the head, avoiding pressure points. Furthermore, instead of using focal IRL delivery points via fiberoptic cables, lasers, or light-emitting diodes, the distribution of the IRL across the entire area of the IDW allows uniform IRL delivery through the skin and into the brain, preventing "hot spots" and thus skin burns. The IRL delivery waveguides have unique design features, including optimized IRL extraction step numbers and angles and a protective housing. The design can be scaled to fit various treatment areas, providing a novel IRL delivery interface platform. Using fresh (unfixed) human cadavers and isolated cadaver tissues, we tested transmission of IRL via IDWs in comparison to laser beam application with fiberoptic cables. Using the same IRL output energies IDWs performed superior in comparison to the fiberoptic delivery, leading to an up to 95% and 81% increased IRL transmission for 750 and 940 nm IRL, respectively, analyzed at a depth of 4 cm into the human head. We discuss the unique safety features and potential further improvements of the IDWs for future clinical implementation.

Listening to Music Pretask on Neuromuscular Fatigue During Exercise: Preferred vs. Nonpreferred Music.

ABSTRACT: Diehl, TL, Yu, JN, Storer, FM, and Malek, MH. Listening to music pretask on neuromuscular fatigue during exercise: preferred vs. nonpreferred music. J Strength Cond Res 37(7): 1537-1542, 2023-Studies indicate that listening to music can elicit various physiological responses ranging from distracting the subject from the sensation of fatigue to changes in specific regions of the brain. Indeed, the use of music, as an ergogenic aid, to improve human performance has been shown to be a powerful tool. Many studies on the effect of music on human performance have had subjects listen to music in-task (i.e., during the activity). There is, however, a growing interest to determine the role of listening to music pretask (i.e., before the activity) on exercise outcomes. In addition, it is important to consider the subject's music preference as that may influence the target outcome variable(s). Therefore, the purpose of this study was to determine whether listening to preferred music pretask influences the physical working capacity at the fatigue threshold (PWC FT ). We hypothesized that listening to preferred music pretask will increase the estimated PWC FT compared with the control condition, which is listening to nonpreferred music. Nine healthy college-aged men (mean ± SEM : age, 23.4 ± 0.4 years; body mass, 71.6 ± 2.5 kg; and height, 1.81 ± 0.02 m) volunteered for this study. Each subject visited the laboratory on 2 occasions separated by 7 days. In a randomized manner, subjects listened to their preferred music for 30 minutes before the exercise test for 1 visit, whereas for the other visit, subjects listened to their nonpreferred music 30 minutes before the exercise test. Exercise outcomes were recorded for both visits and analyzed using a paired-samples t test. The results indicated no significant ( p > 0.05) mean differences for maximal power output (mean ± SEM : 60 ± 4 W vs. 60 ± 4 W), PWC FT (25 ± 3 W vs. 29 ± 2 W), or heart rate at end exercise (153 ± 8 b·min -1 vs. 155 ± 7 b·min -1 ) between listening to nonpreferred vs. preferred music 30 minutes before the exercise activity. These findings suggest that listening to music pretask does not influence neuromuscular fatigue during the exercise workbout.

Sometimes less is more: inhibitory infrared light during early reperfusion calms hyperactive mitochondria and suppresses reperfusion injury.

Ischemic stroke affects over 77 million people annually around the globe. Due to the blockage of a blood vessel caused by a stroke, brain tissue becomes ischemic. While prompt restoration of blood flow is necessary to save brain tissue, it also causes reperfusion injury. Mitochondria play a crucial role in early ischemia-reperfusion injury due to the generation of reactive oxygen species (ROS). During ischemia, mitochondria sense energy depletion and futilely attempt to up-regulate energy production. When reperfusion occurs, mitochondria become hyperactive and produce large amounts of ROS which damages neuronal tissue. This ROS burst damages mitochondria and the cell, which results in an eventual decrease in mitochondrial activity and pushes the fate of the cell toward death. This review covers the relationship between the mitochondrial membrane potential (ΔΨm) and ROS production. We also discuss physiological mechanisms that couple mitochondrial energy production to cellular energy demand, focusing on serine 47 dephosphorylation of cytochrome c (Cytc) in the brain during ischemia, which contributes to ischemia-reperfusion injury. Finally, we discuss the use of near infrared light (IRL) to treat stroke. IRL can both stimulate or inhibit mitochondrial activity depending on the wavelength. We emphasize that the use of the correct wavelength is crucial for outcome: inhibitory IRL, applied early during reperfusion, can prevent the ROS burst from occurring, thus preserving neurological tissue.

Log-Transformed Electromyography Amplitude Power Output Relationship: Nondominant vs. Dominant Limb.

ABSTRACT: Boccomino, HL, Daoud, BT, Hudas, A, North, WA, and Malek, MH. Log-transformed electromyography amplitude power output relationship: nondominant vs. dominant limb. J Strength Cond Res 36(3): 851-856, 2022-Findings from studies that examine bilateral differences between the nondominant and dominant limb during whole-body (i.e., cycle ergometry) are equivocal. This may, in part, be because of the mode of exercise (i.e., whole-body) and how the data are analyzed. Surface electromyography (EMG) is a noninvasive method of examining motor unit recruitment and activation during exercise. The log-transformed electromyography amplitude power output relationship provides y-intercept and slope terms on a subject-by-subject basis that can therefore be statistically analyzed. The purpose of this study, therefore, was to identify potential differences in the muscle for the nondominant and dominant limb using the log-transformed EMG amplitude power output relationship for continuous exercise that isolates the quadricep femoris muscles. Nine healthy college-aged men (mean ± SEM: age, 22.6 ± 1.2 years; mass, 68.6 ± 10.4 kg; and height, 1.76 ± 0.03 m) volunteered as subjects for the current study. Each subject visited the laboratory on a single occasion, had EMG electrodes placed on their rectus femoris muscle for their nondominant and dominant limb, and performed an incremental double-leg knee-extensor ergometry to voluntary exhaustion. The subjects achieved a mean power output (75 ± 8 W) for the exercise test. In addition, a mean end-exercise heart rate (155 ± 8 b·min-1) corresponded to 79 ± 4% of the age-predicted heart rate using the formula 220-age. Separate paired t tests for the slope (t[8] = 0.929 p = 0.38) and y-intercept (t[8] = 0.368, p = 0.72) terms revealed no significant mean differences between the 2 limbs. The results of the present study indicate that there are no differences in muscle activation between the nondominant and dominant limbs for continuous exercise that isolates the muscle.

Perceived Consumption of a High-Dose Caffeine Drink Delays Neuromuscular Fatigue.

ABSTRACT: Elhaj, HM, Imam, O, Page, BW, Vitale, JM, and Malek, MH. Perceived consumption of a high-dose caffeine drink delays neuromuscular fatigue. J Strength Cond Res 36(5): 1185-1190, 2022-The placebo effect is a concept in which a desired outcome arises, mainly from the belief that the treatment (i.e., supplement or drug) was beneficial although no active ingredient was given. The results of studies related to the placebo effect primarily examine functional performance. What remains unanswered, however, is whether these changes in performance are associated with neuromuscular alterations in the exercised muscles. The purpose of the study, therefore, was to determine the influence of the placebo effect on the physical working capacity fatigue threshold (PWCFT) for a continuous exercise paradigm. To achieve this aim, subjects were told that they were participating in a study to determine the dosage response (low or high) of caffeine on neuromuscular fatigue when in fact no caffeine was given during the experiment. We hypothesized that the perceived consumption of the high-dose caffeine drink would result in a higher PWCFT than the perceived consumption of the low-dose caffeine drink and placebo. Secondarily, we hypothesized that the perceived consumption of the high-dose caffeine drink would result in a higher power output than the perceived consumption of the placebo. Nine healthy college-aged men (mean ± SEM: age, 25.7 ± 1.3 years; body mass, 84.4 ± 3.1 kg; and height: 1.82 ± 0.02 m) volunteered to be in the study. For each of the visits, subjects were given an 8 oz. bottle of water with dissolved crystal light. After the drink was consumed, subjects rested in the laboratory for 1 hour before performing the incremental single-leg knee-extensor ergometry. Immediately after the termination of the incremental single-leg knee-extensor ergometry, the subject was asked which caffeine dose (placebo, low, or high) they believed they consumed for that visit. There were no significant mean differences for maximal power output for the 3 perceived conditions (placebo: 62 ± 3, low-dose caffeine: 62 ± 4, and high-dose caffeine: 65 ± 3 W). When the subjects perceived consuming the high-dose caffeine drink, there were significant mean differences (all p-values < 0.01), for PWCFT, between the other conditions (mean ± SEM: placebo: 23 ± 3 W, low-dose caffeine: 26 ± 2 W, and high-dose caffeine: 42 ± 3 W). This corresponded to a significant mean difference (all p-values < 0.01) when the PWCFT was presented as a percentage of the maximal power output (mean ± SEM: placebo: 37 ± 5%, low-dose caffeine: 42 ± 3%, and high-dose caffeine: 64 ± 3%). The application of our results may indicate that the subject's expectancy, to caffeine consumption, plays a critical role in delaying the onset of neuromuscular fatigue despite not receiving any caffeine in their drinks.

Evaluating Subjective and Objective Fatigue Immediately Before and After Hemodialysis: A Within-Subjects' Design.

Change in fatigue within a hemodialysis (HD) session has not been established previously. A total of 55 cognitively intact adults on HD were included; individuals with mobility/hemodynamic issues were excluded. Measures included the Piper Fatigue Scale-12 (PFS-12), 6-Minute Walk Test (6MWT), demographic and clinical. Descriptive statistics, ANOVA, and stepwise regression were used. Mean age was 57 years. Mean change in PFS-12 was -4.56 ± 27.85. Mean change in walk distance was -16.26 ± 43.87 meters (p = 0.03). The change in the PFS-12 accounted for 47% quadratic trend in the change in 6MWD (p < 0.001). Both fatigue measures (PFS-12 and 6MWT) can be useful for examining changes in fatigue levels within an HD session. Our findings speak to the convergent validity of these two measures of fatigue.

The Evolution of the Physical Work Capacity at the Fatigue Threshold Test: Past, Present, and Future.

ABSTRACT: Feldpausch, JE, Blok, AL, Frederick, EL, Coburn, JW, and Malek, MH. The evolution of the physical work capacity at the fatigue threshold test: past, present, and future. J Strength Cond Res 35(12): 3529-3536, 2021-The assessment of neuromuscular fatigue using surface electromyography has evolved over the past 40 years while maintaining some of the original key features. In this mini-review article, the goal will be to briefly present a history and systems of the physical working capacity at the fatigue threshold (PWCFT). In addition, we will discuss studies that have investigated the effect of different interventions such as supplementation, exercise, and cognitive fatigue to examine what stimuli influence the PWCFT. The latter section of this mini-review will discuss future studies that may provide additional information related to the underlying physiological mechanism(s) that influences the PWCFT. We will conclude with the practical application of PWCFT in health and sports settings.

Reduced Electromyographic Fatigue Threshold After Performing a Cognitive Fatiguing Task.

ABSTRACT: Ferris, JR, Tomlinson, MA, Ward, TN, Pepin, ME, and Malek, MH. Reduced electromyographic fatigue threshold after performing a cognitive fatiguing task. J Strength Cond Res 35(1): 267-274, 2021-Cognitive fatigue tasks performed before exercise may reduce exercise capacity. The electromyographic fatigue threshold (EMGFT) is the highest exercise intensity that can be maintained without significant increase in the electromyography (EMG) amplitude vs. time relationship. To date, no studies have examined the effect of cognitive fatigue on the estimation of the EMGFT. The purpose of this study, therefore, was to determine whether cognitive fatigue before performing exercise reduces the estimated EMGFT. Eight healthy college-aged men were recruited from a university student population and visited the laboratory on multiple occasions. In a randomized order, subjects performed either the cognitive fatigue task (AX continuous performance test) for 60 minutes on one visit (experimental condition) or watched a video on trains for 60 minutes on the other visit (control condition). After each condition, subjects performed the incremental single-leg knee-extensor ergometry test while the EMG amplitude was recorded from the rectus femoris muscle and heart rate was monitored throughout. Thereafter, the EMGFT was calculated for each subject for each visit and compared using paired samples t-test. For exercise outcomes, there were no significant mean differences for maximal power output between the 2 conditions (control: 51 ± 5 vs. fatigue: 50 ± 3 W), but there was a significant decrease in EMGFT between the 2 conditions (control: 31 ± 3 vs. fatigue: 24 ± 2 W; p = 0.013). Moreover, maximal heart rate was significantly different between the 2 conditions (control: 151 ± 5 vs. fatigue: 132 ± 6; p = 0.027). These results suggest that performing the cognitive fatiguing task reduces the EMGFT with a corresponding reduction in maximal heart rate response.

Pre-exhaustion Exercise Differentially Influences Neuromuscular Fatigue Based on Habitual Physical Activity History.

ABSTRACT: Harlan, KG, Merucci, RB, Weaver, JJ, Windle, TC, and Malek, MH. Pre-exhaustion exercise differentially influences neuromuscular fatigue based on habitual physical activity history. J Strength Cond Res 35(3): 739-745, 2021-Although there is anecdotal evidence of a potential physiological benefit of pre-exhaustion exercise to enhance muscular recruitment, few studies have systematically examined the effect on neuromuscular activity. Moreover, a subject's habitual physical activity history may, in part, contribute to the muscle's response on a subsequent workbout after a single pre-exhaustion workbout. To date, no studies have examined the effect of pre-exhaustion exercise on the electromyographic fatigue threshold (EMGFT). The purpose of this study, therefore, is to determine whether pre-exhaustion exercise influences the EMGFT. Specifically, we were interested in determining whether or not there is a dichotomous response to pre-exhaustion exercise based on the individual's habitual physical activity history. Thus, we hypothesized that healthy active subjects would have reduced EMGFT values, whereas elite runners would have increased EMGFT values as a result of the pre-exhaustion exercise. Eight healthy college-aged men (mean ± SEM, age = 24.5 ± 0.3 years; body mass = 83.1 ± 3.0 kg; and height = 1.80 ± 0.02 m) and 9 elite runners (mean ± SEM, age = 23.4 ± 0.7 years; body mass = 70.3 ± 2.7 kg; and height = 1.79 ± 0.03 m) participated in current study. Each subject visited the laboratory on 2 occasions separated by 7 days and performed the single-leg knee-extensor ergometry test. For one of the visits, the subjects performed the Thorstensson test (50 continuous, concentric knee extensions) before the single-leg knee-extensor ergometry. The EMGFT was measured on both visits for all subjects. For healthy subjects, we found that the EMGFT was significantly reduced after performing the 50 isokinetic knee extensions (control: 27 ± 6 W vs. Thorstensson: 21 ± 6.0 W; p = 0.001), whereas for elite runners, there was no significant mean differences between the 2 visits (control: 38 ± 3 W vs. Thorstensson: 39 ± 2 W; p = 0.813). These results suggest that 50 repetition of isokinetic muscle action, as a method of pre-exhausting the quadriceps femoris muscles, may be influenced by the subject's habitual exercise history.

Repeated Incremental Workbouts Separated by 1 Hour Increase the Electromyographic Fatigue Threshold.

ABSTRACT: Bremer, N, Peoples, G, Hasler, B, Litzenburg, R, Johnson, A, and Malek, MH. Repeated incremental workbouts separated by 1 hour increase the electromyographic fatigue threshold. J Strength Cond Res 35(5): 1397-1402, 2021-Studies examining the influence of priming, for continuous exercise, have mainly focused on improved exercise capacity related to oxygen uptake kinetics rather than on neuromuscular fatigue of the muscle. The purpose of this study, therefore, was to determine whether or not the electromyographic fatigue threshold (EMGFT) could be modulated by having subjects perform 2 incremental tests separated by 1 hour. We hypothesized that the EMGFT determined from the second incremental test would be higher than the EMGFT determined from the first incremental test. Nine healthy college-aged men (mean ± SEM: age: 23.8 ± 0.6 years; body mass: 79.5 ± 3.3 kg; height: 1.78 ± 0.02 m) were recruited from the university population. Each subject visited the laboratory on 1 occasion and performed 2 incremental single-leg knee-extensor ergometry to voluntary fatigue separated by 1 hour. The EMGFT was determined for each trial and statistically compared using paired-samples t-test. The results indicated significant mean differences between the EMGFT for the 2 trials (trial 1: 27 ± 1 W vs. trial 2: 34 ± 2 W; p = 0.001), whereas there were no significant mean differences for maximal power output (trial 1: 53 ± 2 W vs. trial 2: 57 ± 2; p = 0.09). These findings suggest that postactivation potentiation may, in part, explain the differences in EMGFT because the exercise mode used in the current study minimizes the cardiorespiratory responses to exercise.

Cytochrome c oxidase-modulatory near-infrared light penetration into the human brain: Implications for the noninvasive treatment of ischemia/reperfusion injury.

Near-infrared light (IRL) has been evaluated as a therapeutic for a variety of pathological conditions, including ischemia/reperfusion injury of the brain, which can be caused by an ischemic stroke or cardiac arrest. Strategies have focused on modulating the activity of mitochondrial electron transport chain (ETC) enzyme cytochrome c oxidase (COX), which has copper centers that broadly absorb IRL between 700 and 1,000 nm. We have recently identified specific COX-inhibitory IRL wavelengths that are profoundly neuroprotective in rodent models of brain ischemia/reperfusion through the following mechanism: COX inhibition by IRL limits mitochondrial membrane potential hyperpolarization during reperfusion, which otherwise causes reactive oxygen species (ROS) production and cell death. Prior to clinical application of IRL on humans, IRL penetration must be tested, which may be wavelength dependent. In the present study, four fresh (unfixed) cadavers and isolated cadaver tissues were used to examine the transmission of infrared light through human biological tissues. We conclude that the transmission of 750 and 940 nm IRL through 4 cm of cadaver head supports the viability of IRL to treat human brain ischemia/reperfusion injury and is similar for skin with different skin pigmentation. We discuss experimental difficulties of working with fresh cadavers and strategies to overcome them as a guide for future studies.

Multiple Dimensions and Correlates of Fatigue in Individuals on Hemodialysis.

This study examined the severity, pattern, and correlates of fatigue among adults undergoing hemodialysis. Measures included the Piper Fatigue Scale (PFS-12), Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue, Charlson Comorbidity Index, and Six-Minute Walk Test (6MWT). Patients were excluded if mobility or cardiovascular issues prevented conducting the 6MWT. Participants were 86 cognitively intact adults (M = 61.7 years, SD = 13.81), predominantly male (58.1%), and African American (48.8%), with 80% reporting fatigue in the week prior to hemodialysis. Significant increases were noted in sensory and cognitive fatigue from pre- to post-dialysis, while the 6MWT distance decreased significantly pre- to post-dialysis. Factors significantly associated with pre-dialysis fatigue included low hemoglobin, younger age, and living with someone else, while comorbidities and dialysis inadequacy were trending to significant associations with fatigue.

Epigenetic Responses to Acute Resistance Exercise in Trained vs. Sedentary Men.

Bagley, JR, Burghardt, KJ, McManus, R, Howlett, B, Costa, PB, Coburn, JW, Arevalo, JA, Malek, MH, and Galpin, AJ. Epigenetic responses to acute resistance exercise in trained vs. sedentary men. J Strength Cond Res 34(6): 1574-1580, 2020-Acute resistance exercise (RE) alters DNA methylation, an epigenetic process that influences gene expression and regulates skeletal muscle adaptation. This aspect of cellular remodeling is poorly understood, especially in resistance-trained (RT) individuals. The study purpose was to examine DNA methylation in response to acute RE in RT and sedentary (SED) young men, specifically targeting genes responsible for metabolic, inflammatory, and hypertrophic muscle adaptations. Vastus lateralis biopsies were performed before (baseline), 30 minutes after, and 4 hours after an acute RE bout (3 × 10 repetitions at 70% 1 repetition maximum [1RM] leg press and leg extension) in 11 RT (mean ± SEM: age = 26.1 ± 1.0 years; body mass = 84.3 ± 0.2 kg; leg press 1RM = 412.6 ± 25.9 kg) and 8 SED (age = 22.9 ± 1.1 years; body mass = 75.6 ± 0.3 kg; leg press 1RM = 164.8 ± 22.5 kg) men. DNA methylation was analyzed through methylation sensitive high-resolution melting using real-time polymerase chain reaction. Separate 2 (group) × 3 (time) repeated-measures analyses of variance and analyses of covariance were performed to examine changes in DNA methylation for each target gene. Results showed that acute RE (a) hypomethylated LINE-1 (measure of global methylation) in RT but not SED, (b) hypermethylated metabolic genes (GPAM and SREBF2) in RT, while lowering SREBF2 methylation in SED, and (c) did not affect methylation of genes associated with inflammation (IL-6 and TNF-α) or hypertrophy (mTOR and AKT1). However, basal IL-6 and TNF-α were lower in SED compared with RT. These findings indicate the same RE stimulus can illicit different epigenetic responses in RT vs. SED men and provides a molecular mechanism underpinning the need for differential training stimuli based on subject training backgrounds.

Listening to Fast-Tempo Music Delays the Onset of Neuromuscular Fatigue.

Centala, J, Pogorel, C, Pummill, SW, and Malek, MH. Listening to fast-tempo music delays the onset of neuromuscular fatigue. J Strength Cond Res 34(3): 617-622, 2020-Studies determining the effect of music on physical performance have primarily focused on outcomes such as running time to exhaustion, blood lactate, or maximal oxygen uptake. The electromyographic fatigue threshold (EMGFT) is determined through a single incremental test and operationally defined as the highest exercise intensity that can be sustained indefinitely without an increase in EMG activity of the working muscle. To date, no studies have examined the role of fast-tempo music on EMGFT. The purpose of this investigation, therefore, was to determine whether fast-tempo music attenuates neuromuscular fatigue as measured by the EMGFT. We hypothesized that listening to fast-tempo music during exercise would increase the estimated EMGFT compared with the control condition. Secondarily, we hypothesized that maximal power output would also increase as a result of listening to fast-tempo music during the exercise workbout. Ten healthy college-aged men (mean ± SEM: age, 25.3 ± 0.8 years [range from 22 to 31 years]; body mass, 78.3 ± 1.8 kg; height: 1.77 ± 0.02 m) visited the laboratory on 2 occasions separated by 7 days. The EMGFT was determined from an incremental single-leg knee-extensor ergometer for each visit. In a randomized order, subjects either listened to music or no music for the 2 visits. All music was presented as instrumentals and randomized with a tempo ranging between 137 and 160 b·min. The results indicated that listening to fast-tempo music during exercise increased maximal power output (No Music: 48 ± 4; Music: 54 ± 3 W; p = 0.02) and EMGFT (No Music: 27 ± 3; Music: 34 ± 4 W; p = 0.008). There were, however, no significant mean differences between the 2 conditions (no music vs. music) for absolute and relative end-exercise heart rate as well as end-exercise rating of perceived exertion for the exercised leg. These findings suggest that listening to fast-tempo music increased overall exercise tolerance as well as the neuromuscular fatigue threshold. The results are applicable to both sport and rehabilitative settings.

Log-Transformed Electromyography Amplitude-Power Output Relationship: Single-Leg Knee-Extensor Versus Single-Leg Cycle Ergometry.

Noble, EB, Pilarski, JM, Vora, HK, Zuniga, JM, and Malek, MH. Log-transformed electromyography amplitude-power output relationship: single-leg knee-extensor versus single-leg cycle ergometry. J Strength Cond Res 33(5): 1311-1319, 2019-Comparing and contrasting motor unit recruitment and activation for the same muscles for multiple versus single-joint exercise may provide a better understanding of neuromuscular fatigue. The purpose of this study, therefore, is to compare the slope and y-intercept terms for the 3 superficial quadriceps femoris (QF) (vastus lateralis, rectus femoris, and vastus medialis) muscles derived from the log-transformed electromyography (EMG) amplitude-power output relationship between the single-leg knee-extensor ergometry (KE) and the single-leg cycle ergometry (CE). Ten healthy college-aged men who engaged in regular physical activity visited the laboratory on 2 occasions separated by 7 days to perform either single-leg CE or single-leg KE in a randomized order. For each visit, subjects performed incremental exercise until voluntary fatigue. Electromyography electrodes were placed on the superficial QF muscles. The slope and y-intercept terms, for each muscle, for the EMG amplitude versus power output relationship was examined using the log-transformed model for each subject's data. The results indicated no significant (p > 0.05) mean differences for either slope or y-intercept terms between exercise modes and across muscles. In addition, separate repeated-measures analyses of variance (ANOVAs) were used to determine mean differences for the slope and y-intercept values between the 3 muscles. In addition, separate 2 (mode: CE or KE) × intensity (intensity: 30, 60, and 90% of maximal workload) repeated-measures ANOVAs were conducted for each muscle. There was a significant (p < 0.05) mode × exercise intensity interaction for each muscle. Follow-up testing indicated that in most cases, the normalized EMG amplitude was significantly higher for single-leg KE than single-leg CE. These results indicated that incremental single-leg KE activates the superficial QF muscles significantly greater than single-leg CE.

Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis.

Cytochrome c (Cyt c) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cyt c has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cyt c is tightly regulated by allosteric mechanisms, tissue-specific isoforms, and post-translational modifications (PTMs). Distinct residues of Cyt c are modified by PTMs, primarily phosphorylations, in a highly tissue-specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨm), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia-reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cyt c. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cyt c and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm, limiting ROS generation. We examine the role of Cyt c PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.-Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis.