Skeletal muscle atrophy in clinical and preclinical models of chronic kidney disease: A systematic review and meta-analysis.

Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed sarcopenia. The extent of skeletal muscle wasting in clinical and preclinical CKD populations is unclear. We evaluated skeletal muscle atrophy in preclinical and clinical models of CKD, with multiple sub-analyses for muscle mass assessment methods, CKD severity, sex and across the different preclinical models of CKD. We performed a systematic literature review of clinical and preclinical studies that measured muscle mass/size using the following databases: Ovid Medline, Embase and Scopus. A random effects meta-analysis was utilized to determine standard mean difference (SMD; Hedges' g) between healthy and CKD. Heterogeneity was evaluated using the I2 statistic. Preclinical study quality was assessed via the Systematic Review Centre for Laboratory Animal Experimentation and clinical studies quality was assessed via the Newcastle-Ottawa Scale. This study was registered in PROSPERO (CRD42020180737) prior to initiation of the search. A total of 111 studies were included in this analysis using the following subgroups: 106 studies in the primary CKD analysis, 18 studies that accounted for diabetes and 7 kidney transplant studies. Significant atrophy was demonstrated in 78% of the preclinical studies and 49% of the clinical studies. The random effects model demonstrated a medium overall SMD (SMD = 0.58, 95% CI = 0.52-0.64) when combining clinical and preclinical studies, a medium SMD for the clinical population (SMD = 0.48, 95% CI = 0.42-0.55; all stages) and a large SMD for preclinical CKD (SMD = 0.95, 95% CI = 0.76-1.14). Further sub-analyses were performed based upon assessment methods, disease status and animal model. Muscle atrophy was reported in 49% of the clinical studies, paired with small mean differences. Preclinical studies reported significant atrophy in 78% of studies, with large mean differences. Across multiple clinical sub-analyses such as severity of CKD, dialysis modality and diabetes, a medium mean difference was found. Sub-analyses in both clinical and preclinical studies found a large mean difference for males and medium for females suggesting sex-specific implications. Muscle atrophy differences varied based upon assessment method for clinical and preclinical studies. Limitations in study design prevented conclusions to be made about the extent of muscle loss with disease progression, or the impact of dialysis. Future work would benefit from the use of standardized measurement methods and consistent clinical staging to improve our understanding of atrophy changes in CKD progression, and analysis of biological sex differences.

Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

BACKGROUND: 25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3, and cardiovascular functional and structural endpoints in patients with CKD. METHODS: We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: <0.4 ng/mL, n = 51; Q2: 0.4 ng/mL, n = 26; Q3: 0.5-0.7 ng/mL, n = 47; Q4: ≥0.8 ng/mL, n = 41). Patients in Q1 exhibited lower peak oxygen uptake [VO2Peak = 18.4 (16.2-20.8) mL/min/kg] compared with Q4 [20.8 (18.6-23.2) mL/min/kg; P = .009]. Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR [from 0.47 (0.30) ng/mL to 0.90 (0.45) ng/mL] and declined in NTWC [from 0.61 (0.32) ng/mL to 0.45 (0.29) ng/mL; P < .001]. Serum 3-epi-25(OH)D3 was associated with VO2Peak longitudinally in both groups [KTR: ß (standard error) = 2.53 (0.56), P < .001; NTWC: 2.73 (0.70), P < .001], but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)2D3 and the 25(OH)D3:24,25(OH)2D3 ratio were not associated with any cardiovascular outcome (all P > .05). CONCLUSIONS: Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

Relationship between klotho and physical function in healthy aging.

Epidemiological studies have reported a strong association between circulating Klotho and physical function; however, the cohorts were comprised of older adults with multiple comorbidities. Herein, we examined the relationship between Klotho and physical function in a community-based cohort of healthy adults. In this cross-sectional study, serum Klotho was measured in 80 adults who visited the Musculoskeletal Function, Imaging, and Tissue Resource Core of the Indiana Center for Musculoskeletal Health. Participants (n = 20, 10 [50%] men per group) were chosen into four age groups: 20-34, 35-49, 50-64, and ≥ 65 years, and were further grouped based on performance (low vs. high) on grip strength and chair stand tests. Klotho levels were lower in the ≥ 65 years group (703.0 [189.3] pg/mL; p = 0.022) and the 50-64 years group (722.6 [190.5] pg/mL; p = 0.045) compared to 20-34 years (916.1 [284.8] pg/mL). No differences were observed in Klotho between the low and high performers. The ≥ 65 years group walked a shorter distance during the 6-min walk test (6MWT) compared to 20-34 years (p = 0.005). Klotho was correlated with age (p < 0.001), body fat (p = 0.037), and 6MWT distance (p = 0.022). Klotho levels decline as early as the fifth decade of life, potentially before the onset of age-related impairment in exercise capacity.

Skeletal Muscle Complications in Chronic Kidney Disease.

PURPOSE OF REVIEW: To provide an overview of the recent literature investigating the pathophysiology of skeletal muscle changes, interventions for skeletal muscle, and effects of exercise in chronic kidney disease (CKD). RECENT FINDINGS: There are multiple CKD-related changes that negatively impact muscle size and function. However, the variability in the assessment of muscle size, in particular, hinders the ability to truly understand the impact it may have in CKD. Exercise interventions to improve muscle size and function demonstrate inconsistent responses that warrant further investigation to optimize exercise prescription. Despite progress in the field, there are many gaps in the knowledge of the pathophysiology of sarcopenia of CKD. Identifying these gaps will help in the design of interventions that can be tested to target muscle loss and its consequences such as impaired mobility, falls, and poor quality of life in patients with CKD.

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.

Background The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross-sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low-frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min-1·1.73 m-2), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage >12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min-1·kg-1) compared with predialysis (22.7 [5.2] mL·min-1·kg-1; P<0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index (P<0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage >12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min-1·kg-1) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min-1·kg-1; P=0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low-risk New York Heart Association class I and higher-risk New York Heart Association class II to IV heart failure.

Comparison of the lymphocyte response to interval exercise versus continuous exercise in recreationally trained men.

The purpose of this investigation was to compare changes in circulating lymphocyte subset cell counts between high-intensity interval exercise (HIIE), sprint interval exercise (SIE), and moderate-intensity continuous exercise (MICE). Recreationally active men (n â€‹= â€‹11; age: 23 â€‹± â€‹4 â€‹yr; height: 179.9 â€‹± â€‹4.5 â€‹cm; body mass: 79.8 â€‹± â€‹8.7 â€‹kg; body fat %:12.6 â€‹± â€‹3.8%; V̇O2max: 46.6 â€‹± â€‹3.9 â€‹ml⋅kg-1⋅min-1) completed a maximal graded exercise test to determine maximal oxygen uptake (V̇O2max) and three duration-matched cycling trials (HIIE, SIE, and MICE) in a randomized, counterbalanced fashion. HIIE consisted of fifteen 90-s bouts at 85% V̇O2max interspersed with 90-s active recovery periods. SIE consisted of fifteen 20-s bouts at 130% maximal power and 160-s active recovery periods. MICE was a continuous bout at 65% V̇O2max. Total exercise duration was 53 â€‹min in all three trials, including warm-up and cool-down. Blood was collected before, immediately post, 30 â€‹min, 2 â€‹h, 6 â€‹h, and 24 â€‹h post-exercise. Changes in lymphocyte subset counts, and surface expression of various markers were analyzed via flow cytometry. Changes were assessed using mixed model regression analysis with an autoregressive first order repeated measures correction. Significant decreases were observed in absolute counts of CD56dim NK cells, CD19+ B cells, CD4+ T cells, and CD8+ T cells 30 â€‹min and 24-h post-exercise in all three trials. Despite resulting in greater total work and oxygen consumption, MICE elicited similar changes in lymphocyte subset counts and receptor expression compared to both SIE and HIIE. Similarly, while the two interval trials resulted in differing oxygen consumption and total work, no differences in the lymphocyte response were observed. Though both forms of exercise resulted in declines in circulating lymphocyte cell counts, neither exercise type provides an immune-related advantage when matched for duration.

Relationships Between Hex Bar Deadlift One-Repetition Maximum and Maximal Isometric Pulls.

This study sought to determine relationships between hexagonal barbell (HBB) deadlift one-repetition maximum (1-RM) and force-time characteristics of maximal isometric pulls. Twenty-three healthy adults (13 men [8 trained], 10 women [4 trained]) completed three visits consisting of a familiarization and anthropometrics session, a HBB deadlift 1-RM session, and a performance session with three maximal isometric pulls at three positions: lift-off (FLOOR), knee-passing (KNEE), and mid-thigh (MT). Correlation analyses assessed relationships between 1-RM and force-time characteristics at each position with significance set a priori at α ≤ 0.05. Correlation coefficients between 1-RM and force-time characteristics at all positions presented large to very large relationships to peak force (PF; r = 0.695-0.879, p ≤ 0.001), large to very large relationships to all time-specific force variables (r = 0.506-0.812; p ≤ 0.014), moderate to very large relationships between rate of force development (RFD) time-bands (r = 0.430-0.752; p ≤ 0.041), and large to very large relationships to impulse (r = 0.575-0.778; p ≤ 0.004). Collectively, more very large effect sizes (r = 0.7-0.89) were observed at FLOOR (n = 8) and KNEE (n = 6) than MT (n = 0). PF at FLOOR and KNEE presented as strongest predictors of maximal strength in the 1-RM HBB deadlift. The observed differences between positions may be due to exercise-specific disadvantageous positions commonly observed as isometric sticking points. Coaches should consider incorporating isometric pulls from the lift-off or knee passing positions as it appears to be better related to maximal strength than the isometric mid-thigh pull.

Klotho: An Emerging Factor With Ergogenic Potential.

Sarcopenia and impaired cardiorespiratory fitness are commonly observed in older individuals and patients with chronic kidney disease (CKD). Declines in skeletal muscle function and aerobic capacity can progress into impaired physical function and inability to perform activities of daily living. Physical function is highly associated with important clinical outcomes such as hospitalization, functional independence, quality of life, and mortality. While lifestyle modifications such as exercise and dietary interventions have been shown to prevent and reverse declines in physical function, the utility of these treatment strategies is limited by poor widespread adoption and adherence due to a wide variety of both perceived and actual barriers to exercise. Therefore, identifying novel treatment targets to manage physical function decline is critically important. Klotho, a remarkable protein with powerful anti-aging properties has recently been investigated for its role in musculoskeletal health and physical function. Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, endothelial function, oxidative stress, and inflammation. This is particularly important for older adults and patients with CKD, which are known states of Klotho deficiency. Emerging data support the existence of Klotho-related benefits to exercise and for potential Klotho-based therapeutic interventions for the treatment of sarcopenia and its progression to physical disability. However, significant gaps in our understanding of Klotho must first be overcome before we can consider its potential ergogenic benefits. These advances will be critical to establish the optimal approach to future Klotho-based interventional trials and to determine if Klotho can regulate physical dysfunction.

Tumor necrosis factor-α, TNF receptor, and soluble TNF receptor responses to aerobic exercise in the heat.

The purpose of this study was to evaluate the effects of aerobic exercise in the heat on circulating concentrations of tumor necrosis factor (TNF)-α, soluble TNF receptors (STNFR1&2), and surface expression of TNFR1&2 on monocyte subpopulations. Twelve recreationally active Caucasian men (24.4 ± 3.4 yrs.; 180.0 ± 6.8 cm; 81.5 ± 8.0 kg; 47.2 ± 4.8 mL·kg-1·min-1) completed an exercise protocol in three environmental conditions: high temperature/low humidity [HTLH; 35 °C, 20% relative humidity (RH)]; high temperature/moderate humidity (HTMH; 35 °C, 45%RH); and moderate temperature/moderate humidity (MTMH; 22 °C, 45%RH). Each protocol consisted of a 60-minute cycling trial at 60% VO2max, a 15-minute rest, and a time-to-exhaustion trial at 90% VO2max (TTE). Blood was sampled before (PRE), immediately after (POST) the 60-minute trial, immediately post-TTE (PTTE), and one-hour post-TTE (REC). Circulating TNF-α and STNFR1&2 were assayed. TNFR1&2 expression on monocyte subsets was measured by flow cytometry on a subset of participants (n = 8). TNF-α area under the curve with respect to increase (AUCi) was greater during HTMH compared to MTMH and HTLH. STNFR1 concentration was greater during HTMH compared to MTMH. With all trials combined, STNFR1 concentration increased from PRE to POST, PTTE, and REC. TNFR1 expression on non-classical monocytes was greater during HTMH compared to HTLH while TNFR2 expression was lower during HTLH compared to both MTMH and HTMH. Data suggest that exercise in the heat increases circulating TNF-α and STNFR1 concentration concomitantly. Furthermore, non-classical monocyte expression of TNFRs are impacted by temperature and humidity during exercise.

Effects of supine rest duration on ultrasound measures of the vastus lateralis.

INTRODUCTION: Due to the potential for intramuscular fluid shifts from changing body position, researchers often utilize a 10- to 15-min period of supine rest as a standardizing procedure prior to ultrasound assessment of the lower limbs. However, no previous research has observed the changes in muscle morphological characteristics via ultrasonography of the lower limbs depending on the length of time of supine rest to determine whether 10-15 min of supine rest is necessary. The aim of this study was to examine changes in muscle morphology of the vastus lateralis (VL) at various time-points over the course of 15 min of supine rest. METHODS: Muscle thickness (MT), cross-sectional area (CSA) and echo intensity (EI) of the VL were assessed in 24 adults at four time-points including the following: immediately upon moving from a standing to supine position (T0), after 5 (T5), 10 (T10) and 15 min (T15) of lying in a supine position. RESULTS: CSA significantly decreased from T0 to T10 (P = 0·001) and T15 (P<0·001), with no difference between any other time-points (P = 0·055-0·666). However, the reported changes in CSA did not exceed the standard error of the measurement for this procedure. No significant differences between any time-points for MT (P = 0·726-0·966) or EI (P = 0·061-0·783) were observed. DISCUSSION: These findings suggest extended periods of supine rest may not be needed to obtain consistent muscle morphological measurements of the VL using ultrasonography.

Tumor necrosis factor-alpha and soluble TNF-alpha receptor responses in young vs. middle-aged males following eccentric exercise.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) has been shown to be implicated in both muscle regeneration and muscle wasting. However, it remains unclear whether TNF-α is responsible for the age-related losses in muscle size and function. Also, due to the high clearance rate of TNF-α from circulation, analyzing the circulating levels of soluble TNF-α receptors 1 and 2 (STNFR1 and STNFR2) may provide a better indication of inflammatory events. The aim of this study was to examine changes in circulating concentrations of TNF-α, STNFR1, and STNFR2 following acute eccentric exercise in young (YA) and middle-aged (MA) men. METHODS AND MATERIALS: Nine YA (N=9, 21.8±2.2y, 179.5±4.9cm, 91.2±12.2kg, 21.8±4.3% body fat) and ten MA (N=10, 47.0±4.4y, 176.8±7.6cm; 96.0±21.5kg, 25.4±5.3% body fat) men completed an acute muscle damaging protocol (MDP). Blood samples were obtained at baseline (BL), immediately (IP), 30-minute (30P), 60-minute (60P), 120-minute (120P), 24-hour (24H), and 48-hour (48H) post-MDP. Lower body performance was assessed via isokinetic dynamometer at BL, IP, 120P, 24H, and 48H. RESULTS: YA displayed higher values of peak torque (p=0.023) and mean torque (p=0.036) at BL. No significant group differences were observed for markers of muscle damage or TNF-α. Plasma concentrations of TNF-α were unchanged following MDP. STNFR1 concentrations were significantly higher in the YA group compared to MA (p=0.036). Significant time effects were observed for STNFR1 (p<0.001) and STNFR2 (p=0.001). With both groups combined, serum STNFR1 was decreased at 30P (p=0.001), while STNFR2 was decreased at 30P (p=0.008), 60P (p=0.003), and 120P (p=0.002) relative to BL. CONCLUSIONS: The pro-inflammatory response to muscle damage does not appear to decline at middle age when individuals are recreationally trained. However, young men showed significantly higher serum STNFR1 concentrations than middle age men. This may suggest that natural inhibitors of TNF-α decline as early as middle age.

Comparisons in the Recovery Response From Resistance Exercise Between Young and Middle-Aged Men.

Gordon, JA III, Hoffman, JR, Arroyo, E, Varanoske, AN, Coker, NA, Gepner, Y, Wells, AJ, Stout, JR, and Fukuda, DH. Comparisons in the recovery response from resistance exercise between young and middle-aged men. J Strength Cond Res 31(12): 3454-3462, 2017-The purpose of this study was to compare the effects of a bout of high-volume isokinetic resistance exercise protocol (HVP) on lower-body strength and markers of inflammation and muscle damage during recovery between young and middle-aged adult men. Nineteen recreationally trained men were classified as either a young adult (YA: 21.8 ± 2.0 years; 90.7 ± 11.6 kg) or a middle-aged adult (MA: 47.0 ± 4.4 years; 96.0 ± 21.5 kg) group. The HVP consisted of 8 sets of 10 repetitions, with 1 minute of rest between each set, performed on an isokinetic dynamometer at 60°·s. Maximal voluntary isometric contractions and isokinetic peak torque (PKT) and average torque (AVGT) (measured at 240° and 60°·s, respectively) were assessed at baseline (BL), immediately post (IP), 120 minutes, 24, and 48 hours after HVP. Blood was obtained at BL, IP, 30, 60, 120 minute, 24, and 48 hours after HVP to assess muscle damage and inflammation. All performance data were analyzed using repeated measures analysis of covariance, whereas all inflammatory and muscle damage markers were analyzed using a 2-way (time × group) repeated measures analysis of variance. Results revealed no between-group differences for PKT, AVGT, or rate of torque development at 200 ms (RTD200). No between-group differences in myoglobin, creatine kinase, C-reactive protein, or interleukin-6 were observed. Although BL differences in muscle performance were observed between YA and MA, no between-group differences were noted in performance recovery measures from high-volume isokinetic exercise in recreationally trained men. These results also indicate that the inflammatory and muscle damage response from high-volume isokinetic exercise is similar between recreationally trained, young, and middle-aged adult men.

Comparison of the recovery response from high-intensity and high-volume resistance exercise in trained men.

PURPOSE: The purpose of this study was to compare the physiological responses of a high-volume (HV; 8 sets of 10 repetitions) versus high-intensity (HI; 8 sets of 3 repetitions) exercise protocol in resistance-trained men. METHODS: Twelve men (24.5 ± 4.2 years; 82.3 ± 8.4 kg; 175.2 ± 5.5 cm) with 6.3 ± 3.4 years of resistance training experience performed each protocol in a counterbalanced, randomized order. Performance [counter movement jump peak power (CMJP), isokinetic (ISOK) and isometric leg extension (MVIC), isometric mid-thigh pull (IMTP), and isometric squat (ISQ)] and muscle morphological [cross-sectional area (CSA) of vastus lateralis] assessments were performed at baseline (BL), 30-min (P-30 min), 24-h (P-24 h), 48-h (P-48 h), and 72-h (P-72 h) post-exercise for each testing session. In addition, endocrine (testosterone and cortisol), inflammatory [interleukin-6 (IL-6) and C-reactive protein (CRP)], and markers of muscle damage [creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin (Mb)] were assessed at the same time points. RESULTS: Significantly greater reductions in CMJP (p < 0.001), and peak torque during both ISOK (p = 0.003) and MVIC (p = 0.008) at P-30 min were detected in HV compared to HI protocol. MVIC was still impaired at P-72 h following the HV protocol, while no differences were noted following HI. Markers of muscle damage (LDH, CK, and Mb) were significantly elevated following both HV and HI (p < 0.05), while cortisol and IL-6 concentrations were significantly elevated at P-30 min following HV only (p < 0.001 and p < 0.05, respectively). CONCLUSIONS: Results indicate that high-volume resistance exercise results in greater performance deficits, and a greater extent of muscle damage, than a bout of high-intensity resistance exercise.