Skeletal muscle vulnerability in a child with Pitt-Hopkins syndrome.

BACKGROUND: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. METHOD: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. RESULTS: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. CONCLUSION: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.

Competing endogenous RNA networks were associated with fat accumulation in skeletal muscle of aged male mice.

Muscle aging contributed to morbidity and mortality in the elderly adults by leading to severe outcomes such as frailty, falls and fractures. Post-transcriptional regulation especially competing endogenous RNA (ceRNA) mechanism may modulate the process of skeletal muscle aging. RNA-seq was performed in quadriceps of 6-month-old (adult) and 22-month-old (aged) male mice to identify differentially expressed ncRNAs and mRNAs and further construct ceRNA networks. Decreased quadriceps-body weight ratio and muscle fiber cross-sectional area as well as histological characteristics of aging were observed in the aged mice. Besides, there were higher expressions of atrogin-1 and MuRF-1 and lower expression of Myog, Myf4 and Myod1 in the quadriceps of aged mice relative to that of adult mice. The expression of 85 lncRNAs, 52 circRNAs, 10 miRNAs and 277 mRNAs were significantly dysregulated in quadriceps between the two groups, among which two ceRNA networks lncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were constructed. Level of triglycerides and expression of PPARγ, C/EBPα, FASN and leptin were elevated and the expression of adiponectin was reduced in quadriceps of aged mice compared with that of adult mice. LncRNA 2700081O15Rik/circRNA_0000820-miR-673-3p-Tmem120b were possibly associated with the adipogenesis and fat accumulation in skeletal muscle of age male mice.

Effects of Alaska Pollack Protein Ingestion on Neuromuscular Adaptation in Young Healthy Adults: A Randomized, Placebo-Controlled Trial.

Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study aimed to examine the effects of APP ingestion on muscle quantity and quality in young adults. Fifty-five young college students were assigned to two groups: APP and placebo (whey protein: WP) groups, and instructed to ingest 4.5 g of each protein in addition to daily meals, and to maintain their usual daily physical activities for 3 mo. Twenty-one and 23 students completed the intervention and were analyzed in APP and WP groups, respectively. The maximum knee extension torque significantly increased in both groups during the intervention. The motor unit discharge rate, which is an indicator of activation, for a given force level significantly decreased in both groups during the intervention, but its decrease in the APP group was significantly greater than in the WP group. Echo intensity of the vastus lateralis evaluated by ultrasound images significantly decreased in both groups. The muscle thickness and skeletal muscle mass did not change. Small amount of additional APP intake induces greater effects on neural activation than WP, suggesting the greater neural economy of generation of force.

Acute neuromuscular, cardiovascular, and muscle oxygenation responses to low-intensity aerobic interval exercises with blood flow restriction.

We investigated the influence of short- and long-interval cycling exercise with blood flow restriction (BFR) on neuromuscular fatigue, shear stress and muscle oxygenation, potent stimuli to BFR-training adaptations. During separate sessions, eight individuals performed short- (24 × 60 s/30 s; SI) or long-interval (12 × 120 s/60 s; LI) trials on a cycle ergometer, matched for total work. One leg exercised with (BFR-leg) and the other without (CTRL-leg) BFR. Quadriceps fatigue was quantified using pre- to post-interval changes in maximal voluntary contraction (MVC), potentiated twitch force (QT) and voluntary activation (VA). Shear rate was measured by Doppler ultrasound at cuff release post-intervals. Vastus lateralis tissue oxygenation was measured by near-infrared spectroscopy during exercise. Following the initial interval, significant (P < 0.05) declines in MVC and QT were found in both SI and LI, which were more pronounced in the BFR-leg, and accounted for approximately two-thirds of the total reduction at exercise termination. In the BFR-leg, reductions in MVC (-28 ± 15%), QT (-42 ± 17%), and VA (-15 ± 17%) were maximal at exercise termination and persisted up to 8 min post-exercise. Exercise-induced muscle deoxygenation was greater (P < 0.001) in the BFR-leg than CTRL-leg and perceived pain was more in LI than SI (P < 0.014). Cuff release triggered a significant (P < 0.001) shear rate increase which was consistent across trials. Exercise-induced neuromuscular fatigue in the BFR-leg exceeded that in the CTRL-leg and was predominantly of peripheral origin. BFR also resulted in diminished muscle oxygenation and elevated shear stress. Finally, short-interval trials resulted in comparable neuromuscular and haemodynamic responses with reduced perceived pain compared to long-intervals.

Influence of intramuscular steroid receptor content and fiber capillarization on skeletal muscle hypertrophy.

Multiple intramuscular variables have been proposed to explain the high variability in resistance training induced muscle hypertrophy across humans. This study investigated if muscular androgen receptor (AR), estrogen receptor α (ERα) and ß (ERß) content and fiber capillarization are associated with fiber and whole-muscle hypertrophy after chronic resistance training. Male (n = 11) and female (n = 10) resistance training novices (22.1 ± 2.2 years) trained their knee extensors 3×/week for 10 weeks. Vastus lateralis biopsies were taken at baseline and post the training period to determine changes in fiber type specific cross-sectional area (CSA) and fiber capillarization by immunohistochemistry and, intramuscular AR, ERα and ERß content by Western blotting. Vastus lateralis volume was quantified by MRI-based 3D segmentation. Vastus lateralis muscle volume significantly increased over the training period (+7.22%; range: -1.82 to +18.8%, p < 0.0001) but no changes occurred in all fiber (+1.64%; range: -21 to +34%, p = 0.869), type I fiber (+1.33%; range: -24 to +41%, p = 0.952) and type II fiber CSA (+2.19%; range: -23 to +29%, p = 0.838). However, wide inter-individual ranges were found. Resistance training increased the protein expression of ERα but not ERß and AR, and the increase in ERα content was positively related to changes in fiber CSA. Only for the type II fibers, the baseline capillary-to-fiber-perimeter index was positively related to type II fiber hypertrophy but not to whole muscle responsiveness. In conclusion, an upregulation of ERα content and an adequate initial fiber capillarization may be contributing factors implicated in muscle fiber hypertrophy responsiveness after chronic resistance training.

Physiologic Determinants of Near-Infrared Spectroscopy-Derived Cerebral and Tissue Oxygen Saturation Measurements in Critically Ill Patients.

OBJECTIVES: Near-infrared spectroscopy (NIRS) is a potentially valuable modality to monitor the adequacy of oxygen delivery to the brain and other tissues in critically ill patients, but little is known about the physiologic determinants of NIRS-derived tissue oxygen saturations. The purpose of this study was to assess the contribution of routinely measured physiologic parameters to tissue oxygen saturation measured by NIRS. DESIGN: An observational sub-study of patients enrolled in the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomized feasibility trial. SETTING: Two ICUs in the United Kingdom. PATIENTS: Patients were recruited for the RADAR-2 study, which compared a conservative approach to fluid therapy and deresuscitation with usual care. Those included in this sub-study underwent continuous NIRS monitoring of cerebral oxygen saturations (SctO2) and quadriceps muscle tissue saturations (SmtO2). INTERVENTION: Synchronized and continuous mean arterial pressure (MAP), heart rate (HR), and pulse oximetry (oxygen saturation, Spo2) measurements were recorded alongside NIRS data. Arterial Paco2, Pao2, and hemoglobin concentration were recorded 12 hourly. Linear mixed effect models were used to investigate the association between these physiologic variables and cerebral and muscle tissue oxygen saturations. MEASUREMENTS AND MAIN RESULTS: Sixty-six patients were included in the analysis. Linear mixed models demonstrated that Paco2, Spo2, MAP, and HR were weakly associated with SctO2 but only explained 7.1% of the total variation. Spo2 and MAP were associated with SmtO2, but together only explained 0.8% of its total variation. The remaining variability was predominantly accounted for by between-subject differences. CONCLUSIONS: Our findings demonstrated that only a small proportion of variability in NIRS-derived cerebral and tissue oximetry measurements could be explained by routinely measured physiologic variables. We conclude that for NIRS to be a useful monitoring modality in critical care, considerable further research is required to understand physiologic determinants and prognostic significance.

Muscle strength, quantity and quality and muscle fat quantity and their association with oxidative stress in patients with facioscapulohumeral muscular dystrophy: Effect of antioxidant supplementation.

The purpose of this study was to identify causes of quadriceps muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). To this aim, we evaluated quadriceps muscle and fat volumes by magnetic resonance imaging and their relationships with muscle strength and oxidative stress markers in adult patients with FSHD (n = 32) and healthy controls (n = 7), and the effect of antioxidant supplementation in 20 of the 32 patients with FSHD (n = 10 supplementation and n = 10 placebo) (NCT01596803). Compared with healthy controls, the dominant quadriceps strength and quality (muscle strength per unit of muscle volume) were decreased in patients with FSHD. In addition, fat volume was increased, without changes in total muscle volume. Moreover, in patients with FSHD, the lower strength of the non-dominant quadriceps was associated with lower muscle quality compared with the dominant muscle. Antioxidant supplementation significantly changed muscle and fat volumes in the non-dominant quadriceps, and muscle quality in the dominant quadriceps. This was associated with improved muscle strength (both quadriceps) and antioxidant response. These findings suggest that quadriceps muscle strength decline may not be simply explained by atrophy and may be influenced also by the muscle intrinsic characteristics. As FSHD is associated with increased oxidative stress, supplementation might reduce oxidative stress and increase antioxidant defenses, promoting changes in muscle function.

Curcumin regulates autophagy through SIRT3-SOD2-ROS signaling pathway to improve quadriceps femoris muscle atrophy in KOA rat model.

Knee osteoarthritis (KOA) usually leads to quadriceps femoris atrophy, which in turn can further aggravate the progression of KOA. Curcumin (CUR) has anti-inflammatory and antioxidant effects and has been shown to be a protective agent for skeletal muscle. CUR has been shown to have a protective effect on skeletal muscle. However, there are no studies related to whether CUR improves KOA-induced quadriceps femoris muscle atrophy. We established a model of KOA in rats. Rats in the experimental group were fed CUR for 5 weeks. Changes in autophagy levels, reactive oxygen species (ROS) levels, and changes in the expression of the Sirutin3 (SIRT3)-superoxide dismutase 2 (SOD2) pathway were detected in the quadriceps femoris muscle of rats. KOA led to quadriceps femoris muscle atrophy, in which autophagy was induced and ROS levels were increased. CUR increased SIRT3 expression, decreased SOD2 acetylation and ROS levels, inhibited the over-activation of autophagy, thereby alleviating quadriceps femoris muscle atrophy and improving KOA. CUR has a protective effect against quadriceps femoris muscle atrophy, and KOA is alleviated after improvement of quadriceps femoris muscle atrophy, with the possible mechanism being the reduction of ROS-induced autophagy via the SIRT3-SOD2 pathway.

The effects of resistance training on denervated myofibers, senescent cells, and associated protein markers in middle-aged adults.

Denervated myofibers and senescent cells are hallmarks of skeletal muscle aging. However, sparse research has examined how resistance training affects these outcomes. We investigated the effects of unilateral leg extensor resistance training (2 days/week for 8 weeks) on denervated myofibers, senescent cells, and associated protein markers in apparently healthy middle-aged participants (MA, 55 ± 8 years old, 17 females, 9 males). We obtained dual-leg vastus lateralis (VL) muscle cross-sectional area (mCSA), VL biopsies, and strength assessments before and after training. Fiber cross-sectional area (fCSA), satellite cells (Pax7+), denervated myofibers (NCAM+), senescent cells (p16+ or p21+), proteins associated with denervation and senescence, and senescence-associated secretory phenotype (SASP) proteins were analyzed from biopsy specimens. Leg extensor peak torque increased after training (p < .001), while VL mCSA trended upward (interaction p = .082). No significant changes were observed for Type I/II fCSAs, NCAM+ myofibers, or senescent (p16+ or p21+) cells, albeit satellite cells increased after training (p = .037). While >90% satellite cells were not p16+ or p21+, most p16+ and p21+ cells were Pax7+ (>90% on average). Training altered 13 out of 46 proteins related to muscle-nerve communication (all upregulated, p < .05) and 10 out of 19 proteins related to cellular senescence (9 upregulated, p < .05). Only 1 out of 17 SASP protein increased with training (IGFBP-3, p = .031). In conclusion, resistance training upregulates proteins associated with muscle-nerve communication in MA participants but does not alter NCAM+ myofibers. Moreover, while training increased senescence-related proteins, this coincided with an increase in satellite cells but not alterations in senescent cell content or SASP proteins. These latter findings suggest shorter term resistance training is an unlikely inducer of cellular senescence in apparently healthy middle-aged participants. However, similar study designs are needed in older and diseased populations before definitive conclusions can be drawn.

The effect of neuromuscular electrical stimulation on the human skeletal muscle transcriptome.

AIM: The influence on acute skeletal muscle transcriptomics of neuromuscular electrical stimulation (NMES), as compared to established exercises, is poorly understood. We aimed to investigate the effects on global mRNA-expression in the quadriceps muscle early after a single NMES-session, compared to the effects of voluntary knee extension exercise (EX), and to explore the discomfort level. METHODS: Global vastus lateralis muscle gene expression was assessed (RNA-sequencing) in 30 healthy participants, before and 3 h after a 30-min session of NMES and/or EX. The NMES-treatment was applied using textile electrodes integrated in pants and set to 20% of each participant's pre-tested MVC mean (±SD) 200 (±80) Nm. Discomfort was assessed using Visual Analogue Scale (VAS, 0-10). The EX-protocol was performed at 80% of 1-repetition-maximum. RESULTS: NMES at 20% of MVC resulted in VAS below 4 and induced 4448 differentially expressed genes (DEGs) with 80%-overlap of the 2571 DEGs of EX. Genes well-known to be up-regulated following exercise, for example, PPARGC1A, ABRA, VEGFA, and GDNF, were also up-regulated by NMES. Gene set enrichment analysis demonstrated many common pathways after EX and NMES. Also, some pathways were exclusive to either EX, for example, muscle tissue proliferation, or to NMES, for example, neurite outgrowth and connective tissue proliferation. CONCLUSION: A 30-min NMES-session at 20% of MVC with NMES-pants, which can be applied with an acceptable level of discomfort, induces over 4000 DEGs, of which 80%-overlap with DEGs of EX. NMES can induce exercise-like molecular effects, that potentially can lead to health and performance benefits in individuals who are unable to perform resistance exercise.

Physiological and Metabolic Responses to Low-Volume Sprint Interval Exercises: Influence of Sprint Duration and Repetitions.

PURPOSE: This study aimed to determine physiological and metabolic responses to two different sprint interval exercises (SIE) matched for total sprint duration and sprint-rest ratio. METHODS: After having measured peak oxygen uptake (V̇O 2peak ), 14 healthy males (27.1 ± 4.8 yr, 169.6 ± 6.0 cm, 64.5 ± 8.4 kg, V̇O 2peak : 47.2 ± 7.7 mL·kg -1 ·min -1 ) performed four 10-s sprints with 80-s recovery (SIE10) and two 20-s sprints with 160-s recovery (SIE20) on different occasions in a counterbalanced crossover manner. Pulmonary V̇O 2 and changes in tissue oxygenation index (∆TOI) at vastus lateralis (VL) and rectus femoris (RF) were measured during the SIE. Furthermore, T2-weighted magnetic resonance imaging was taken immediately before and after the SIE to determine the activation levels of VL, RF, vastus medialis, vastus intermedius, adductor magnus, biceps femoris long head, semitendinosus, and semimembranosus at 50% of right thigh length. RESULTS: In SIE10, increases in V̇O 2 and ∆TOI at VL and RF plateaued after the second sprint, whereas session-averaged ∆TOI was greater in SIE20 than SIE10 in both muscles (VL: 20.9 ± 7.4 vs 14.2% ± 5.9%, RF: 22.8 ± 9.3 vs 12.9% ± 6.6%, P = 0.00). Although both SIE significantly increased T2 values in all eight muscles, those magnitudes were similar between the conditions (SIE10 vs SIE20: 5%-16% vs 8%-16%). CONCLUSIONS: This study showed blunted responses of whole-body (V̇O 2 ) and peripheral (∆TOI) oxidative responses with successive sprints (sprint 1 < sprints 2-4) in SIE10, suggesting that increasing sprint repetitions does not necessarily induce greater oxidative metabolism or stimulus. Moreover, greater peripheral oxygen extraction (∆TOI) was achieved with SIE20, whereas %changes of T2 indicates that the thigh muscles were similarly activated between the SIE conditions.

Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.

In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and contribution from anaerobic metabolism affects utilisation of the distinct pools. Furthermore, we investigated how decreased glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise affect the storage of glycogen particles (size, numerical density, localisation). Twenty participants were divided into two groups performing either a 1-min (n = 10) or a 15-min (n = 10) maximal cycling exercise test. In a randomised, counterbalanced, cross-over design, the exercise tests were performed following short-term consumption of two distinct diets with either high or moderate carbohydrate content (10 vs. 4 g kg-1 body mass (BM) day-1) mediating a difference in total energy consumption (240 vs. 138 g kg-1 BM day-1). Muscle biopsies from m. vastus lateralis were obtained before and after the exercise tests. Intermyofibrillar glycogen was preferentially utilised during the 1-min test, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min test. Lowering carbohydrate and energy intake after glycogen-depleting exercise reduced glycogen availability by decreasing particle size across all pools and diminishing numerical density in the intramyofibrillar and subsarcolemmal pools. In conclusion, distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal cycling exercise. Additionally, lowered carbohydrate and energy consumption after glycogen-depleting exercise altered glycogen storage by reducing particle size and numerical density, depending on subcellular localisation. KEY POINTS: In human skeletal muscle, glycogen particles are localised in distinct subcellular compartments, referred to as intermyofibrillar, intramyofibrillar and subsarcolemmal pools. The intermyofibrillar and subsarcolemmal pools are close to mitochondria, while the intramyofibrillar pool is at a distance from mitochondria. We show that 1 min of maximal exercise is associated with a preferential utilisation of intermyofibrillar glycogen, and, on the other hand, that 15 min of maximal exercise is associated with a preferential utilisation of intramyofibrillar glycogen. Furthermore, we demonstrate that reduced glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise is characterised by a decreased glycogen particle size across all compartments, with the numerical density only diminished in the intramyofibrillar and subsarcolemmal compartments. These results suggest that exercise intensity influences the subcellular pools of glycogen differently and that the dietary content of carbohydrates and energy is linked to the size and subcellular distribution of glycogen particles.

Hemodynamic and neuromuscular basis of reduced exercise capacity in patients with end-stage renal disease.

PURPOSE: The present study aimed to characterize the exercise-induced neuromuscular fatigue and its possible links with cerebral and muscular oxygen supply and utilization to provide mechanistic insights into the reduced exercise capacity characterizing patients with end-stage renal disease (ESRD). METHODS: Thirteen patients with ESRD and thirteen healthy males (CTR group) performed a constant-force sustained isometric contraction at 50% of their maximal voluntary isometric contraction (MVC) until exhaustion. Quadriceps muscle activation during exercise was estimated from vastus lateralis, vastus medialis, and rectus femoris EMG. Central and peripheral fatigue were quantified via changes in pre- to postexercise quadriceps voluntary activation (ΔVA) and quadriceps twitch force (ΔQtw,pot) evoked by supramaximal electrical stimulation, respectively. To assess cerebral and muscular oxygenation, throughout exercise, near-infrared spectroscopy allowed investigation of changes in oxyhemoglobin (∆O2Hb), deoxyhemoglobin (∆HHb), and total hemoglobin (∆THb) in the prefrontal cortex and in the vastus lateralis muscle. RESULTS: ESRD patients demonstrated lower exercise time to exhaustion than that of CTR (88.8 ± 15.3 s and 119.9 ± 14.6 s, respectively, P < 0.01). Following the exercise, MVC, Qtw,pot, and VA reduction were similar between the groups (P > 0.05). There was no significant difference in muscle oxygenation (∆O2Hb) between the two groups (P > 0.05). Cerebral and muscular blood volume (∆THb) and oxygen extraction (∆HHb) were significantly blunted in the ESRD group (P < 0.05). A significant positive correlation was observed between time to exhaustion and cerebral blood volume (∆THb) in both groups (r2 = 0.64, P < 0.01). CONCLUSIONS: These findings support cerebral hypoperfusion as a factor contributing to the reduction in exercise capacity characterizing ESRD patients.

NASA SPRINT exercise program efficacy for vastus lateralis and soleus skeletal muscle health during 70 days of simulated microgravity.

The efficacy of the NASA SPRINT exercise countermeasures program for quadriceps (vastus lateralis) and triceps surae (soleus) skeletal muscle health was investigated during 70 days of simulated microgravity. Individuals completed 6° head-down-tilt bedrest (BR, n = 9), bedrest with resistance and aerobic exercise (BRE, n = 9), or bedrest with resistance and aerobic exercise and low-dose testosterone (BRE + T, n = 8). All groups were periodically tested for muscle (n = 9 times) and aerobic (n = 4 times) power during bedrest. In BR, surprisingly, the typical bedrest-induced decrements in vastus lateralis myofiber size and power were either blunted (myosin heavy chain, MHC I) or eliminated (MHC IIa), along with no change (P > 0.05) in %MHC distribution and blunted quadriceps atrophy. In BRE, MHC I (vastus lateralis and soleus) and IIa (vastus lateralis) contractile performance was maintained (P > 0.05) or increased (P < 0.05). Vastus lateralis hybrid fiber percentage was reduced (P < 0.05) and energy metabolism enzymes and capillarization were generally maintained (P > 0.05), while not all of these positive responses were observed in the soleus. Exercise offsets 100% of quadriceps and approximately two-thirds of soleus whole muscle mass loss. Testosterone (BRE + T) did not provide any benefit over exercise alone for either muscle and for some myocellular parameters appeared detrimental. In summary, the periodic testing likely provided a partial exercise countermeasure for the quadriceps in the bedrest group, which is a novel finding given the extremely low exercise dose. The SPRINT exercise program appears to be viable for the quadriceps; however, refinement is needed to completely protect triceps surae myocellular and whole muscle health for astronauts on long-duration spaceflights.NEW & NOTEWORTHY This study provides unique exercise countermeasures development information for astronauts on long-duration spaceflights. The NASA SPRINT program was protective for quadriceps myocellular and whole muscle health, whereas the triceps surae (soleus) was only partially protected as has been shown with other programs. The bedrest control group data may provide beneficial information for overall exercise dose and targeting fast-twitch muscle fibers. Other unique approaches for the triceps surae are needed to supplement existing exercise programs.

Lower basal and postprandial muscle protein synthesis after 2 weeks single-leg immobilization in older men: No protective effect of anti-inflammatory medication.

Muscle inactivity may reduce basal and postprandial muscle protein synthesis (MPS) rates in humans. Anti-inflammatory treatment alleviates the MPS impairments in younger individuals. The present study explored the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) upon MPS during a period of inactivity in older humans. Eighteen men (age 60-80 years) were allocated to ibuprofen (1200 mg/day, Ibu) or control (Plc) groups. One lower limb was cast immobilized for 2 weeks. Postabsorptive and postprandial MPS was measured before and after the immobilization by L-[ring-13 C6 ]-phenylalanine infusion. The protein expression of select anabolic signaling molecules was investigated by western blot. Basal (0.038 ± 0.002%/h and 0.039 ± 0.005%/h, Plc and Ibu, respectively) and postprandial (0.064 ± 0.004%/h and 0.067 ± 0.010%/h, Plc and Ibu, respectively) MPS rate were higher pre-immobilization compared to basal (0.019 ± 0.005%/h and 0.020 ± 0.010%/h, Plc and Ibu, respectively) and postprandial (0.033 ± 0.005%/h and 0.037 ± 0.006%/h, Plc and Ibu, respectively) MPS rate post-immobilization (p < 0.001). NSAID treatment did not affect the suppression of MPS (p > 0.05). The anabolic signaling were in general reduced after immobilization (p < 0.05). These changes were unaffected by NSAID treatment (p > 0.05). Basal and postprandial MPS dropped markedly after 2 weeks of lower limb immobilization. NSAID treatment neither influenced the reduction in MPS nor the anabolic signaling after immobilization in healthy older individuals.

Downhill running increases markers of muscle damage and impairs the maximal voluntary force production as well as the late phase of the rate of voluntary force development.

PURPOSE: To examined the time-course of the early and late phase of the rate of voluntary force development (RVFD) and muscle damage markers after downhill running. METHODS: Ten recreational runners performed a 30-min downhill run at 10 km h-1 and -20% (-11.3°) on a motorized treadmill. At baseline and each day up to 4 days RVFD, knee extensors maximum voluntary isometric force (MVIC), serum creatine kinase (CK) concentration, quadriceps swelling, and soreness were assessed. The early (0-50 ms) and late (100-200 ms) phase of the RVFD, as well as the force developed at 50 and 200 ms, were also determined. RESULTS: MVIC showed moderate decrements (p < 0.05) and recovered after 4 days (p > 0.05). Force at 50 ms and the early phase were not impaired (p > 0.05). Conversely, force at 200 ms and the late phase showed moderate decrements (p < 0.05) and recovered after 3 and 4 days, respectively (p > 0.05). CK concentration, quadriceps swelling, and soreness increased (p < 0.05) were overall fully resolved after 4 days (p > 0.05). CONCLUSION: Downhill running affected the knee extensors RVFD late but not early phase. The RVFD late phase may be used as an additional marker of muscle damage in trail running.

Age and dietary restriction modulate mitochondrial quality in quadriceps femoris muscle of male mice.

Dietary restriction (DR) is a potential intervention for ameliorating ageing-related damages. Mitochondrial quality control is the key mechanism for regulating cellular functions in skeletal muscle. This study aimed to explore the effect of age and DR on the homeostasis of mitochondrial quality control in skeletal muscle. To study the effect of age on mitochondrial homeostasis, young (3 months old) male C57BL/6J mice were fed ad libitum (AL) until 7 (Young), 14 (Middle), and 19 months (Aged) of age. For the DR intervention, 60% of AL intake was given to the mice at 3 months of age until they reached 19 months of age (16 months). The quadriceps femoris muscle was collected for further analysis. Significant changes in the skeletal muscle were noticed during the transition between middle age and the elderly stages. An accumulation of collagen was observed in the muscle after middle age. Compared with the Middle muscle, Aged muscle displayed a greater expression of VDAC, and lower expressions of mitochondrial dynamic proteins and OXPHOS proteins. The DR intervention attenuated collagen content and elongated the sarcomere length in the skeletal muscle during ageing. In addition, DR adjusted the abnormalities in mitochondrial morphology in the Aged muscle. DR downregulated VDAC expression, but upregulated OPA1 and DRP1 expressions. Taken together, greater pathological changes were noticed in the skeletal muscle during ageing, especially in the transition between middle age and the elderly, whereas early-onset DR attenuated the muscular ageing via normalising partial functions of mitochondria.

Common Markers of Muscle Damage Are Associated with Divergent Gene Expression Patterns after Eccentric Contractions.

PURPOSE: Unaccustomed eccentric (ECC) exercise evokes exercise-induced muscle damage (EIMD). Soreness, strength loss, and serum creatine kinase (CK) are often used to quantify EIMD severity. However, changes in these markers are not fully understood mechanistically. To test the hypothesis that muscle damage markers are associated with unique molecular processes, we correlated gene expression responses with variation in each marker post-ECC. METHODS: Vastus lateralis biopsies were collected from 35 young men 3 h post-ECC (10 sets of 10 maximal eccentric contractions; contralateral leg [CON] as control). Maximal isometric strength, soreness, and serum CK activity were assessed 24 h preexercise and every 24 h for 5 d post-ECC. Strength was also measured 10 min post-ECC. Over the 5 d after ECC, average peak strength loss was 51.5 ± 20%; average soreness increased from 0.9 ± 1.9 on a 100-mm visual analog scale to 39 ± 19; serum CK increased from 160 ± 130 to 1168 ± 3430 U·L -1 . Muscle RNA was used to generate gene expression profiles. Partek Genomics Suite correlated peak values of soreness, strength loss, and CK post-ECC with gene expression in ECC (relative to paired CON) using Pearson linear correlation ( P < 0.05) and repeated-measures ANOVA used to detect influence of ECC. RESULTS: After ECC, 2677 genes correlated with peak soreness, 3333 genes with peak strength loss, and 3077 genes with peak CK. Less than 1% overlap existed across all markers (16/9087). Unique genes included 2346 genes for peak soreness, 3032 genes for peak strength loss, and 2937 genes for peak CK. CONCLUSIONS: The largely unique molecular pathways associated with common indirect markers of EIMD indicate that each marker of "damage" represents unique mechanistic processes.

Alleviation of peripheral sensitization by quadriceps insertion of cog polydioxanone filaments in knee osteoarthritis rats.

A recently established therapeutic strategy, involving the insertion of biodegradable cog polydioxanone filaments into the quadriceps muscles using the Muscle Enhancement and Support Therapy (MEST) device, has demonstrated significant efficacy in alleviating knee osteoarthritis (OA) pain. This study investigated changes in peripheral sensitization as the potential mechanism underlying MEST-induced pain relief in monoiodoacetate (MIA) induced OA rats. The results revealed that MEST treatment potently reduces MIA-induced sensitization of L3/L4 dorsal root ganglion (DRG) neurons, the primary nociceptor pathway for the knee joint. This reduction in DRG sensitization, as elucidated by voltage-sensitive dye imaging, is accompanied by a diminished overexpression of TRPA1 and NaV1.7, key nociceptor receptors involved in mechanical pain perception. Importantly, these observed alterations strongly correlate with a decrease in mechanically-evoked pain behaviors, providing compelling neurophysiological evidence that MEST treatment alleviates OA pain by suppressing peripheral sensitization.

Intermittent normobaric hypoxia alters substrate partitioning and muscle oxygenation in individuals with obesity: implications for fat burning.

This single-blind, crossover study aimed to measure and evaluate the short-term metabolic responses to continuous and intermittent hypoxic patterns in individuals with obesity. Indirect calorimetry was used to quantify changes in resting metabolic rate (RMR), carbohydrate (CHOox, %CHO), and fat oxidation (FATox, %FAT) in nine individuals with obesity pre and post: 1) breathing normoxic air [normoxic sham control (NS-control)], 2) breathing continuous hypoxia (CH), or 3) breathing intermittent hypoxia (IH). A mean peripheral oxygen saturation ([Formula: see text]) of 80-85% was achieved over a total of 45 min of hypoxia. Throughout each intervention, pulmonary gas exchanges, oxygen consumption (V̇o2) carbon dioxide production (V̇co2), and deoxyhemoglobin concentration (Δ[HHb]) in the vastus lateralis were measured. Both RMR and CHOox measured pre- and postinterventions were unchanged following each treatment: NS-control, CH, or IH (all P > 0.05). Conversely, a significant increase in FATox was evident between pre- and post-IH (+44%, P = 0.048). Although the mean Δ[HHb] values significantly increased during both IH and CH (P < 0.05), the greatest zenith of Δ[HHb] was achieved in IH compared with CH (P = 0.002). Furthermore, there was a positive correlation between Δ[HHb] and the shift in FATox measured pre- and postintervention. It is suggested that during IH, the increased bouts of muscle hypoxia, revealed by elevated Δ[HHb], coupled with cyclic periods of excess posthypoxia oxygen consumption (EPHOC, inherent to the intermittent pattern) played a significant role in driving the increase in FATox post-IH.