Daily physical activity and prognostic implications in patients with heart failure: an accelerometer study.

BACKGROUND: Physical activity (PA) measured by accelerometry is proposed as a novel trial endpoint for heart failure (HF). However, standardised methods and associations with established markers are lacking. This study aimed to examine PA measurements and accelerometer repeatability in patients with HF and age- and sex-matched controls, and study correlations with established prognostic HF markers, body composition, and quality of life (QoL). METHODS: Accelerometry was performed in 105 patients with HF with left ventricular ejection fraction (LVEF) ≤ 40% and in 46 controls. Participants also underwent dual X-ray absorptiometry, cardiopulmonary exercise testing, a six-minute walking test (6MWT), echocardiography, and NT-proBNP measurement, and completed a QoL questionnaire. RESULTS: Average acceleration was markedly reduced in patients with HF compared with healthy controls (16.1 ± 4.8 mg vs 27.2 ± 8.5 mg, p < 0.001). Healthy controls spent a median daily 56 min (IQR 41-96 min) in moderate-to-vigorous PA (MVPA), whereas HF patients spent only 12 min (IQR 6-24) in MVPA. In HF patients, average acceleration correlated moderately with 6MWT (R = 0.41, p < 0.001) and maximal oxygen uptake (peak VO2) (R = 0.36, p < 0.001) but not with NT-proBNP, LVEF, or QoL. Patients in NYHA class II showed a higher average acceleration than patients in NYHA III (16.6 ± 4.9 mg vs 14.0 ± 3.6 mg, p = 0.01). CONCLUSIONS: Daily PA was severely reduced in patients with HF compared with healthy controls. In HF patients, we found moderate correlations of accelerometer measurements with markers of physical capacity but not with LVEF or NT-proBNP. TRIAL REGISTRATION: NCT05063955. Registered 01 June 2021-retrospectively registered.

Six weeks of high-load resistance and low-load blood flow restricted training increase Na/K-ATPase sub-units α2 and ß1 equally, but does not alter ClC-1 abundance in untrained human skeletal muscle.

Contractile function of skeletal muscle relies on the ability of muscle fibers to trigger and propagate action potentials (APs). These electrical signals are created by transmembrane ion transport through ion channels and membrane transporter systems. In this regard, the Cl- ion channel 1 (ClC-1) and the Na+/K--ATPase (NKA) are central for maintaining ion homeostasis across the sarcolemma during intense contractile activity. Therefore, this randomized controlled trial aimed to investigate the changes in ClC-1 and specific NKA subunit isoform expression in response to six weeks (18 training sessions) of high-load resistance exercise (HLRE) and low-load blood flow restricted resistance exercise (BFRRE), respectively. HLRE was conducted as 4 sets of 12 repetitions of knee extensions performed at 70% of 1 repetition maximum (RM), while BFRRE was conducted as 4 sets of knee extensions at 30% of 1RM performed to volitional fatigue. Furthermore, the potential associations between protein expression and contractile performance were investigated. We show that muscle ClC-1 abundance was not affected by either exercise modality, whereas NKA subunit isoforms [Formula: see text]2 and [Formula: see text]1 increased equally by appx. 80-90% with BFRRE (p < 0.05) and 70-80% with HLRE (p < 0.05). No differential impact between exercise modalities was observed. At baseline, ClC-1 protein expression correlated inversely with dynamic knee extensor strength (r=-0.365, p = 0.04), whereas no correlation was observed between NKA subunit content and contractile performance at baseline. However, training-induced changes in NKA [Formula: see text]2 subunit (r = 0.603, p < 0.01) and [Formula: see text]1 subunit (r = 0.453, p < 0.05) correlated with exercise-induced changes in maximal voluntary contraction. These results suggest that the initial adaptation to resistance-based exercise does not involve changes in ClC-1 abundance in untrained skeletal muscle, and that increased content of NKA subunits may facilitate increases in maximal force production.

Low-load blood flow-restricted resistance exercise produces fiber type-independent hypertrophy and improves muscle functional capacity in older individuals.

Low-load blood flow-restricted resistance exercise (BFRRE) constitutes an effective means to produce skeletal muscle hypertrophy. Nonetheless, its applicability to counteract the age-related skeletal muscle decay at a cellular level, is not clear. Therefore, we investigated the effect of BFRRE on muscle fiber morphology, integrated muscle protein synthesis, muscle stem cells (MuSCs), myonuclear content, and muscle functional capacity in healthy older individuals. Twenty-three participants with a mean age of 66 yr (56-75 yr) were randomized to 6 wk of supervised BFRRE (3 sessions per week) or non-exercise control (CON). Biopsies were collected from the vastus lateralis before and after the intervention. Immunofluorescent microscopy was utilized to assess muscle fiber type-specific cross-sectional area (CSA) as well as MuSC and myonuclear content. Deuterium oxide was orally administered throughout the intervention period, enabling assessment of integrated myofibrillar and connective tissue protein fractional synthesis rate (FSR). BFRRE produced uniform ∼20% increases in the fiber CSA of both type I and type II fibers (P < 0.05). This occurred concomitantly with improvements in both maximal muscle strength and strength-endurance capacity but in the absence of increased MuSC content and myonuclear addition. The observed muscle fiber hypertrophy was not mirrored by increases in either myofibrillar or connective tissue FSR. In conclusion, BFRRE proved effective in stimulating skeletal muscle growth and increased muscle function in older individuals, which advocates for the use of BFRRE as a countermeasure of age-related deterioration of skeletal muscle mass and function.NEW & NOTEWORTHY We provide novel insight, that as little as 6 wk of low-load blood flow-restricted resistance exercise (BFRRE) produces pronounced fiber type-independent hypertrophy, alongside improvements across a broad range of muscle functional capacity in older individuals. Notably, since these results were obtained with a modest exercise volume and in a very time-efficient manner, BFRRE may represent a potent exercise strategy to counteract age-related muscle decay.

Prolonged loss of force and power following fatiguing contractions in rat soleus muscles. Is low-frequency fatigue an issue during dynamic contractions?

Low-frequency fatigue (LFF) is defined by a relatively larger deficit in isometric force elicited by low-frequency electrical stimulation compared with high-frequency stimulation. However, the effects of LFF on power during dynamic contractions elicited at low and high frequencies have not been thoroughly characterized. In the current study, rat soleus muscles underwent fatiguing either concentric, eccentric, or isometric contractions. Before and 1 h after the fatiguing contractions, a series of brief isometric and dynamic contractions elicited at 20 and 80 Hz stimulation to establish force-velocity relationships. Maximal force (Fmax), velocity (Vmax), and power (Pmax) were assessed for each frequency. Sarcoplasmic reticulum (SR) Ca2+ release and reuptake rates were assessed pre- and postfatigue. Prolonged fatigue was observed as a loss of Fmax and Pmax in muscles fatigued by concentric or eccentric, but not by isometric contractions. When quantified as a decrease in the ratio between 20 Hz and 80 Hz contractile output, LFF was more pronounced for isometric force than for power (-21% vs. -16% for concentrically fatigued muscles, P = 0.003; 29 vs. 13% for eccentrically fatigued muscles, P < 0.001). No changes in SR Ca2+ release or reuptake rates were observed. We conclude that LFF is less pronounced when expressed in terms of power deficits than when expressed in terms of force deficits, and that LFF, therefore, likely affects performance to a lesser degree during fast concentric contractions than during static or slow contractions.

Protein signalling in response to ex vivo dynamic contractions is independent of training status in rat skeletal muscle.

NEW FINDINGS: What is the central question of this study? Are myofibre protein signalling responses to ex vivo dynamic contractions altered by accustomization to voluntary endurance training in rats? What is the main finding and its importance? In response to ex vivo dynamic muscle contractions, canonical myofibre protein signalling pertaining to metabolic transcriptional regulation, as well as translation initiation and elongation, was not influenced by prior accustomization to voluntary endurance training in rats. Accordingly, intrinsic myofibre protein signalling responses to standardized contractile activity may be independent of prior exercise training in rat skeletal muscle. ABSTRACT: Skeletal muscle training status may influence myofibre regulatory protein signalling in response to contractile activity. The current study employed a purpose-designed ex vivo dynamic contractile protocol to evaluate the effect of exercise-accustomization on canonical myofibre protein signalling for metabolic gene expression and for translation initiation and elongation. To this end, rats completed 8 weeks of in vivo voluntary running training versus no running control intervention, whereupon an ex vivo endurance-type dynamic contraction stimulus was conducted in isolated soleus muscle preparations from both intervention groups. Protein signalling response by phosphorylation was evaluated by immunoblotting at 0 and 3 h following ex vivo stimulation. Phosphorylation of AMP-activated protein kinase α-isoforms and its downstream target, acetyl-CoA carboxylase, as well as phosphorylation of eukaryotic elongation factor 2 (eEF2) was increased immediately following the dynamic contraction protocol (at 0 h). Signalling for translation initiation and elongation was evident at 3 h after dynamic contractile activity, as evidenced by increased phosphorylation of p70 S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1, as well as a decrease in phosphorylation of eEF2 back to resting control levels. However, prior exercise training did not alter phosphorylation responses of the investigated signalling proteins. Accordingly, protein signalling responses to standardized endurance-type contractions may be independent of training status in rat muscle during ex vivo conditions. The present findings add to our current understanding of molecular regulatory events responsible for skeletal muscle plasticity.

The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance.

Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification.

Skeletal muscle phenotype signaling with ex vivo endurance-type dynamic contractions in rat muscle.

Skeletal muscle phenotype may influence the response sensitivity of myocellular regulatory mechanisms to contractile activity. To examine this, we employed an ex vivo endurance-type dynamic contraction model to evaluate skeletal muscle phenotype-specific protein signaling responses in rat skeletal muscle. Preparations of slow-twitch soleus and fast-twitch extensor digitorum longus skeletal muscle from 4-wk-old female Wistar rats were exposed to an identical ex vivo dynamic endurance-type contraction paradigm consisting of 40 min of stretch-shortening contractions under simultaneous low-frequency electrostimulation delivered in an intermittent pattern. Phosphorylation of proteins involved in metabolic signaling and signaling for translation initiation was evaluated at 0, 1, and 4 h after stimulation by immunoblotting. For both muscle phenotypes, signaling related to metabolic events was upregulated immediately after stimulation, with concomitant absence of signaling for translation-initiation. Signaling for translation-initiation was then activated in both muscle phenotypes at 1-4 h after stimulation, coinciding with attenuated metabolic signaling. The recognizable pattern of signaling responses support how our ex vivo dynamic muscle contraction model can be utilized to infer a stretch-shortening contraction pattern resembling stretch-shortening contraction of in vivo endurance exercise. Moreover, using this model, we observed that some specific signaling proteins adhering to metabolic events or to translation-initiation exhibited phosphorylation changes in a phenotype-dependent manner, whereas other signaling proteins exhibited phenotype-independent changes. These findings may aid the interpretation of myocellular signaling outcomes adhering to mixed muscle samples collected during human experimental trials.NEW & NOTEWORTHY The application of cyclic ex vivo dynamic muscle contractions delivered in an intermittent pattern may be suitable for the exploration of skeletal muscle regulatory responses to endurance-type contractile activity. In the present study, it is demonstrated that the response to such stimulus of some nodal myocellular signaling proteins related to either metabolic or anabolic signaling events may be influenced by muscle phenotype, whereas the response of others appears to be independent of phenotype.

Concomitant excitation and tension development are required for myocellular gene expression and protein synthesis in rat skeletal muscle.

AIM: Loading-induced tension development is often assumed to constitute an independent cue to initiate muscle protein synthesis following resistance exercise. However, with traditional physiological models of resistance exercise, changes in loading-induced tension development also reflect changes in neural activation patterns, and direct evidence for a mechanosensitive mechanism is therefore limited. Here, we sought to examine the importance of excitation and tension development per se on initiation of signalling, gene transcription and protein synthesis in rat skeletal muscle. METHODS: Isolated rat extensor digitorum longus muscles were allocated to the following interventions: (a) Excitation-induced eccentric contractions (ECC); (b) Passive stretching without excitation (PAS); (c) Excitation with inhibition of contractions (STIM + IMA ) and; (d) Excitation in combination with both inhibition of contractions and PAS (STIM + IMA  + PAS). Assessment of transcriptional and translational signalling, gene transcription and acute muscle protein synthesis was compared in stimulated vs contra-lateral non-stimulated control muscle. RESULTS: Protein synthesis increased solely in muscles subjected to a combination of excitation and tension development (ECC and STIM + IMA  + PAS). The same pattern was true for p38 mitogen-activated protein kinase signalling for gene transcription as well as for gene transcription of immediate early genes FOS and JUN. In contrast, mechanistic target of rapamycin Complex 1 signalling for translation initiation increased in all muscles subjected to increased tension development (ECC and STIM + IMA  + PAS as well as PAS). CONCLUSIONS: The current study suggests that exercise-induced increases in protein synthesis as well as transcriptional signalling is dependent on the concomitant effect of excitation and tension development, whereas signalling for translation initiation is only dependent of tension development per se.

Myocellular Adaptations to Low-Load Blood Flow Restricted Resistance Training.

Low-load blood flow restricted resistance exercise (BFRRE) can stimulate whole-muscle growth and improve muscle function. However, limited knowledge exists on the effects at the myocellular level. We hypothesize that BFRRE has the ability to produce concurrent skeletal muscle myofibrillar, mitochondrial, and microvascular adaptations, thus offering an alternative strategy to counteract decay in skeletal muscle health and function in clinical populations.

Exercise-dependent increases in protein synthesis are accompanied by chromatin modifications and increased MRTF-SRF signalling.

AIM: Resistance exercise increases muscle mass over time. However, the early signalling events leading to muscle growth are not yet well-defined. Here, we aim to identify new signalling pathways important for muscle remodelling after exercise. METHODS: We performed a phosphoproteomics screen after a single bout of exercise in mice. As an exercise model we used unilateral electrical stimulation in vivo and treadmill running. We analysed muscle biopsies from human subjects to verify if our findings in murine muscle also translate to exercise in humans. RESULTS: We identified a new phosphorylation site on Myocardin-Related Transcription Factor B (MRTF-B), a co-activator of serum response factor (SRF). Phosphorylation of MRTF-B is required for its nuclear translocation after exercise and is accompanied by the transcription of the SRF target gene Fos. In addition, high-intensity exercise also remodels chromatin at specific SRF target gene loci through the phosphorylation of histone 3 on serine 10 in myonuclei of both mice and humans. Ablation of the MAP kinase member MSK1/2 is sufficient to prevent this histone phosphorylation, reduce induction of SRF-target genes, and prevent increases in protein synthesis after exercise. CONCLUSION: Our results identify a new exercise signalling fingerprint in vivo, instrumental for exercise-induced protein synthesis and potentially muscle growth.

Utilization of biomarkers as predictors of skeletal muscle mitochondrial content after physiological intervention and in clinical settings.

The measurement of mitochondrial content is essential for bioenergetic research, as it provides a tool to evaluate whether changes in mitochondrial function are strictly due to changes in content or other mechanisms that influence function. In this perspective, we argue that commonly used biomarkers of mitochondrial content may possess limited utility for capturing changes in content with physiological intervention. Moreover, we argue that they may not provide reliable estimates of content in certain pathological situations. Finally, we discuss potential solutions to overcome issues related to the utilization of biomarkers of mitochondrial content. Shedding light on this important issue will hopefully aid conclusions about the mitochondrial structure-function relationship.

Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles.

Ischemic exercise conducted as low-load blood flow restricted resistance exercise (BFRE) can lead to muscle remodelling and promote muscle growth, possibly through activation of muscle precursor cells. Cell activation can be triggered by blood borne extracellular vesicles (EVs) as these nano-sized particles are involved in long distance signalling. In this study, EVs isolated from plasma of healthy human subjects performing a single bout of BFRE were investigated for their change in EV surface profiles and miRNA cargos as well as their impact on skeletal muscle precursor cell proliferation. We found that after BFRE, five EV surface markers and 12 miRNAs were significantly altered. Furthermore, target prediction and functional enrichment analysis of the miRNAs revealed several target genes that are associated to biological pathways involved in skeletal muscle protein turnover. Interestingly, EVs from BFRE plasma increased the proliferation of muscle precursor cells. In addition, alterations in surface markers and miRNAs indicated that the combination of exercise and ischemic conditioning during BFRE can stimulate blood cells to release EVs. These results support that BFRE promotes EV release to engage in muscle remodelling and/or growth processes.

Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia.

Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (ß-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.

Effect of Blood Flow Restricted Resistance Exercise and Remote Ischemic Conditioning on Functional Capacity and Myocellular Adaptations in Patients With Heart Failure.

BACKGROUND: Patients with congestive heart failure (CHF) have impaired functional capacity and inferior quality of life. The clinical manifestations are associated with structural and functional impairments in skeletal muscle, emphasizing a need for feasible rehabilitation strategies beyond optimal anticongestive medical treatment. We investigated whether low-load blood flow restricted resistance exercise (BFRRE) or remote ischemic conditioning (RIC) could improve functional capacity and quality of life in patients with CHF and stimulate skeletal muscle myofibrillar and mitochondrial adaptations. METHODS: We randomized 36 patients with CHF to BFRRE, RIC, or nontreatment control. BFRRE and RIC were performed 3× per week for 6 weeks. Before and after intervention, muscle biopsies, tests of functional capacity, and quality of life assessments were performed. Deuterium oxide was administered throughout the intervention to measure cumulative RNA and subfraction protein synthesis. Changes in muscle fiber morphology and mitochondrial respiratory function were also assessed. RESULTS: BFRRE improved 6-minute walk test by 39.0 m (CI, 7.0-71.1, P=0.019) compared with control. BFRRE increased maximum isometric strength by 29.7 Nm (CI, 10.8-48.6, P=0.003) compared with control. BFRRE improved quality of life by 5.4 points (CI, -0.04 to 10.9; P=0.052) compared with control. BFRRE increased mitochondrial function by 19.1 pmol/s per milligram (CI, 7.3-30.8; P=0.002) compared with control. RIC did not produce similar changes. CONCLUSIONS: Our results demonstrate that BFRRE, but not RIC, improves functional capacity, quality of life, and muscle mitochondrial function. Our findings have clinical implications for rehabilitation of patients with CHF and provide new insights on the myopathy accompanying CHF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03380663.

Six Weeks of Low-Load Blood Flow Restricted and High-Load Resistance Exercise Training Produce Similar Increases in Cumulative Myofibrillar Protein Synthesis and Ribosomal Biogenesis in Healthy Males.

Purpose: High-load resistance exercise contributes to maintenance of muscle mass, muscle protein quality, and contractile function by stimulation of muscle protein synthesis (MPS), hypertrophy, and strength gains. However, high loading may not be feasible in several clinical populations. Low-load blood flow restricted resistance exercise (BFRRE) may provide an alternative approach. However, the long-term protein synthetic response to BFRRE is unknown and the myocellular adaptations to prolonged BFRRE are not well described. Methods: To investigate this, 34 healthy young subjects were randomized to 6 weeks of low-load BFRRE, HLRE, or non-exercise control (CON). Deuterium oxide (D2O) was orally administered throughout the intervention period. Muscle biopsies from m. vastus lateralis were collected before and after the 6-week intervention period to assess long-term myofibrillar MPS and RNA synthesis as well as muscle fiber-type-specific cross-sectional area (CSA), satellite cell content, and myonuclei content. Muscle biopsies were also collected in the immediate hours following single-bout exercise to assess signaling for muscle protein degradation. Isometric and dynamic quadriceps muscle strength was evaluated before and after the intervention. Results: Myofibrillar MPS was higher in BFRRE (1.34%/day, p < 0.01) and HLRE (1.12%/day, p < 0.05) compared to CON (0.96%/day) with no significant differences between exercise groups. Muscle RNA synthesis was higher in BFRRE (0.65%/day, p < 0.001) and HLRE (0.55%/day, p < 0.01) compared to CON (0.38%/day) and both training groups increased RNA content, indicating ribosomal biogenesis in response to exercise. BFRRE and HLRE both activated muscle degradation signaling. Muscle strength increased 6-10% in BFRRE (p < 0.05) and 13-23% in HLRE (p < 0.01). Dynamic muscle strength increased to a greater extent in HLRE (p < 0.05). No changes in type I and type II muscle fiber-type-specific CSA, satellite cell content, or myonuclei content were observed. Conclusions: These results demonstrate that BFRRE increases long-term muscle protein turnover, ribosomal biogenesis, and muscle strength to a similar degree as HLRE. These findings emphasize the potential application of low-load BFRRE to stimulate muscle protein turnover and increase muscle function in clinical populations where high loading is untenable.

Activation of mTORC1 signalling in rat skeletal muscle is independent of the EC-coupling sequence but dependent on tension per se in a dose-response relationship.

AIM: mTORC1 is regarded as an important key regulator of protein synthesis and hypertrophy following mechanical stimuli in skeletal muscle. However, as excitation and tension development is tightly coupled in most experimental models, very little and largely indirect evidence exist for such a mechanosensitive pathway. Here, we sought to examine whether activation of mTORC1 signalling is dependent on tension per se in rat skeletal muscle. METHODS: To examine the mechanosensitivity of mTORC1, rat EDL muscles were exposed to either excitation-induced eccentric contractions (ECC), passive stretching (PAS) with identical peak tension (Tpeak ) and Tension-Time-Integral (TTI), or ECC with addition of inhibitors of the myosin ATPases (IMA ). To further explore the relationship between tension and mTORC1 signalling, rat EDL muscles were subjected to PAS of different magnitudes of Tpeak while standardizing TTI and vice versa. RESULTS: PAS and ECC with equal Tpeak and TTI produced similar responses in mTORC1 signalling despite different modes of tension development. When active tension during ECC was nearly abolished by addition of IMA , mTORC1 signalling was reduced to a level comparable to non-stimulated controls. In addition, when muscles were exposed to PAS of varying levels of Tpeak with standardized TTI, activation of mTORC1 signalling displayed a positive relationship with peak tension. CONCLUSIONS: The current study directly links tension per se to activation of mTORC1 signalling, which is independent of an active EC-coupling sequence. Moreover, activation of mTORC1 signalling displays a positive dose-response relationship with peak tension.

Non-failure blood flow restricted exercise induces similar muscle adaptations and less discomfort than failure protocols.

Low-load blood flow restricted resistance exercise (BFRE) performed to volitional failure is suggested to constitute an effective method for producing increases in muscle size and function. However, BFRE to failure may entail high levels of perceived exertion, discomfort, and/or delayed onset of muscle soreness (DOMS). The aim of the study was to compare BFRE performed to volitional failure (F-BFRE) vs non-failure BFRE (NF-BFRE) on changes in muscle size, function and perceptual responses. Fourteen young untrained males had one leg randomized to knee extension F-BFRE while the contralateral leg performed NF-BFRE. The training consisted of 22 exercise bouts over an 8-week period. Whole-muscle cross-sectional area (CSA) of quadriceps components, muscle function, and DOMS were assessed before and after the training period. Perceived exertion and discomfort were registered during each exercise bout. Both F-BFRE and NF-BFRE produced regional increases in muscle CSA in the range of: quadriceps (2.5%-3.8%), vastus lateralis (8.1%-8.5%), and rectus femoris (7.9%-25.0%). All without differences between leg. Muscle strength (6.8%-11.5%) and strength-endurance capacity (13.9%-18.6%) also increased to a similar degree in both legs. Less perceived exertion, discomfort, and DOMS were reported with NF-BFRE compared to F-BFRE. In conclusion, non-failure BFRE enables increases in muscle size and muscle function, while involving reduced perceptions of exertion, discomfort, and DOMS. Non-failure BFRE may be a more feasible approach in clinical settings.

Changes in metabolism but not myocellular signaling by training with CHO-restriction in endurance athletes.

Carbohydrate (CHO) restricted training has been shown to increase the acute training response, whereas less is known about the acute effects after repeated CHO restricted training. On two occasions, the acute responses to CHO restriction were examined in endurance athletes. Study 1 examined cellular signaling and metabolic responses after seven training-days including CHO manipulation (n = 16). The protocol consisted of 1 h high-intensity cycling, followed by 7 h recovery, and 2 h of moderate-intensity exercise (120SS). Athletes were randomly assigned to low (LCHO: 80 g) or high (HCHO: 415 g) CHO during recovery and the 120SS. Study 2 examined unaccustomed exposure to the same training protocol (n = 12). In Study 1, muscle biopsies were obtained at rest and 1 h after 120SS, and blood samples drawn during the 120SS. In Study 2, substrate oxidation and plasma glucagon were determined. In Study 1, plasma insulin and proinsulin C-peptide were higher during the 120SS in HCHO compared to LCHO (insulin: 0 min: +37%; 60 min: +135%; 120 min: +357%, P = 0.05; proinsulin C-peptide: 0 min: +32%; 60 min: +52%; 120 min: +79%, P = 0.02), whereas plasma cholesterol was higher in LCHO (+15-17%, P = 0.03). Myocellular signaling did not differ between groups. p-AMPK and p-ACC were increased after 120SS (+35%, P = 0.03; +59%, P = 0.0004, respectively), with no alterations in p-p38, p-53, or p-CREB. In Study 2, glucagon and fat oxidation were higher in LCHO compared to HCHO during the 120SS (+26-40%, P = 0.03; +44-76%, P = 0.01 respectively). In conclusion, the clear respiratory and hematological effects of CHO restricted training were not translated into superior myocellular signaling after accustomization to CHO restriction.

Skeletal muscle stem cell characteristics and myonuclei content in patients with rheumatoid arthritis: a cross-sectional study.

To investigate satellite cells (SCs) and myonuclei characteristics in patients with rheumatoid arthritis (RA). Resting biopsies from m. vastus lateralis were obtained from thirteen RA patients and thirteen matched healthy controls (CON). Muscle biopsies were immunohistochemically stained and analyzed for fiber type specific content of SCs (Pax7+), proliferating SCs (Pax7+/MyoD+) and differentiating SCs (myogenin+). Furthermore, we quantified fiber type specific content of myonuclei and myofiber cross-sectional area (CSA). Finally, newly formed/regenerating fibers expressing neonatal MHC (nMHC+) were determined. The fiber type specific number of SCs did not differ between RA patients and CON, nor did the content of proliferating or differentiating SCs. In contrast, the content of myonuclei per fiber was higher in RA patients than CON for both type I (2.01 ± 0.41 vs. 1.42 ± 0.40 myonuclei/fiber, p < 0.01) and type II fibers (2.01 ± 0.41 vs. 1.37 ± 0.32 myonuclei/fiber, p < 0.01). No differences were observed in fiber composition, fiber type specific CSA or content of nMHC+ fibers. Our results indicate an increased propensity for myogenic differentiation of SC leading to an elevated myonuclear content in the skeletal muscle of RA patients. It is hypothesized that this could be a compensatory regulatory response related to the chronic inflammation in these patients.