Near-infrared spectroscopy (NIRS) provides a simple and reliable measure of skeletal muscle oxidative capacity; however, its relationship to aerobic fitness and sex are unclear. We hypothesized that ...NIRS-derived oxidative capacity in the vastus lateralis (VL) and medial gastrocnemius (MG) would be correlated with indices of aerobic fitness and independent of sex. Twenty-six participants (13 males, 13 females) performed ramp- and step-incremental tests to volitional exhaustion on separate days to establish maximal oxygen uptake (V̇o
), peak power output (PPO), lactate threshold (LT), gas exchange threshold (GET), respiratory compensation point (RCP), and maximal fat oxidation (MFO). Data were normalized to lean body mass to account for sex-based differences in body composition. Exercise tests were preceded by duplicate measurements of NIRS-derived oxidative capacity on the VL and MG muscles (i.e., repeated arterial occlusions following a brief set of muscle contractions). Skeletal muscle oxidative capacity for the VL (means ± SD: 21.9 ± 4.6 s) and MG (22.5 ± 6.1 s) were similar but unrelated (
= 0.03,
= 0.39). Skeletal muscle oxidative capacity for the VL, but not the MG (
> 0.05 for all variables), was significantly correlated with V̇o
(
= 0.24;
= 0.01), PPO (
= 0.23;
= 0.01), LT (
= 0.23;
= 0.01), GET (
= 0.23;
= 0.01), and RCP (
= 0.27;
= 0.006). MFO was not correlated with VL or MG skeletal muscle oxidative capacity (
> 0.05). Females (54.9 ± 4.5 mL·kg LBM
·min
) and males (56.0 ± 6.2 mL·kg LBM
·min
), matched for V̇o
(
= 0.62), had similar NIRS-derived oxidative capacities for VL (20.7 ± 4.4 vs. 23.2 ± 4.6 s;
= 0.18) and MG (24.4 ± 6.8 vs. 20.5 ± 4.8 s;
= 0.10). Overall, NIRS-derived skeletal muscle oxidative capacity in VL is indicative of aerobic fitness and independent of sex in humans.
Near-infrared spectroscopy (NIRS) can be used to measure skeletal muscle oxidative capacity. Here, we demonstrated that NIRS-derived skeletal muscle oxidative capacity of the vastus lateralis was independent of sex, reliable across and within days, and correlated with maximal and submaximal indices of aerobic fitness, including maximal oxygen uptake, lactate threshold, and respiratory compensation point. These findings highlight the utility of NIRS for investigating skeletal muscle oxidative capacity in females and males.
ABSTRACT
Few studies have explored the kinetics of performance and perceived fatigability during high‐intensity interval training, despite its popularity. We aimed to characterize the kinetics of ...fatigability and recovery during an 8 × 4‐min HIIT protocol, hypothesizing that most muscle function impairment would occur during the initial four intervals. Fifteen healthy males and females (mean ± standard deviation; age = 26 ± 5 years, V̇O2max = 46.8 ± 6.1 mL·kg−1·min−1) completed eight, 4‐min intervals at 105% of critical power with 3 min of rest. Maximal voluntary knee extension contractions (MVCs) coupled with electrical nerve stimulation were performed at baseline and after the first, fourth, and eighth intervals. MVC, potentiated twitch force (Pt), and Db10:100 ratio all declined throughout HIIT (p < 0.05). MVC sharply declined after interval 1 (−15 ± 9% relative to baseline; p < 0.05) and had only further declined after interval 8 (−26 ± 11%; p < 0.05), but not interval 4 (−19 ± 13%; p > 0.05). Pt and Db10:100 also sharply declined after interval 1 (Pt: −18 ± 13%, Db10:100: −14 ± 20%; p < 0.05) and further declined after interval 4 (Pt: −35 ± 19%, Db10:100: −30 ± 20%; p < 0.05) but not interval 8 (Pt: −41 ± 19%; Db10:100: −32 ± 18%; p > 0.05). Voluntary activation did not significantly change across the HIIT protocol (p > 0.05). Evoked force recovery was significantly blunted as more intervals were completed: after interval 1, Pt recovered by 7 ± 11% compared to −6 ± 7% recovery after interval 8 (p < 0.05). Ratings of perceived effort, fatigue, and leg pain rose throughout the session (p < 0.05 for each) and were greater (effort and fatigue) for females (p < 0.05). Otherwise, males and females exhibited similar performance fatigability kinetics, with contractile function declines blunted in response to additional intervals.
To further refine the near-infrared spectroscopy (NIRS)-derived measure of skeletal muscle oxidative capacity in humans, we sought to determine whether the exercise stimulus intensity affected the τ ...value and/or influenced the magnitude of correlations with in vitro measures of mitochondrial content and in vivo indices of exercise performance. Males (
= 12) and females (
= 12), matched for maximal aerobic fitness per fat-free mass, completed NIRS-derived skeletal muscle oxidative capacity tests for the vastus lateralis following repeated contractions at 40% (τ
) and 100% (τ
) of maximum voluntary contraction, underwent a skeletal muscle biopsy of the same muscle, and performed multiple intermittent isometric knee extension tests to task failure to establish critical torque (CT). The value of τ
(34.4 ± 7.0 s) was greater than τ
(24.2 ± 6.9 s,
< 0.001), but the values were correlated (
= 0.688;
< 0.001). The values of τ
(
= -0.692,
< 0.001) and τ
(
= -0.488,
= 0.016) correlated with myosin heavy chain I percentage and several markers of mitochondrial content, including COX II protein content in whole muscle (τ
:
= -0.547,
= 0.006; τ
:
= -0.466,
= 0.022), type I pooled fibers (τ
:
= -0.547,
= 0.006; τ
:
= -0.547,
= 0.006), and type II pooled fibers (τ
:
= -0.516,
= 0.009; τ
:
= -0.635,
= 0.001). The value of τ
(
= -0.702,
< 0.001), but not τ
(
= -0.378,
= 0.083) correlated with critical torque (CT); however, neither value correlated with W' (τ
:
= 0.071,
= 0.753; τ
:
= 0.054,
= 0.812). Overall, the NIRS method of assessing skeletal muscle oxidative capacity is sensitive to the intensity of skeletal muscle contraction but maintains relationships to whole body fitness, isolated limb critical intensity, and mitochondrial content regardless of intensity.
Skeletal muscle oxidative capacity measured using near-infrared spectroscopy (NIRS) was lower following high-intensity compared with low-intensity isometric knee extension contractions. At both intensities, skeletal muscle oxidative capacity was correlated with protein markers of mitochondrial content (in whole muscle and pooled type I and type II muscle fibers) and critical torque. These findings highlight the importance of standardizing contraction intensity while using the NIRS method with isometric contractions and further demonstrate its validity.
Sprint interval training (SIT) causes fragmentation of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor 1 (RyR1), 24 h post‐exercise, potentially signalling ...mitochondrial biogenesis by increasing cytosolic Ca2+. Yet, the time course and skeletal muscle fibre type‐specific patterns of RyR1 fragmentation following a session of SIT remain unknown. Ten participants (n = 4 females; n = 6 males) performed a session of SIT (6 × 30 s ‘all‐out’ with 4.5 min rest after each sprint) with vastus lateralis muscle biopsy samples collected before and 3, 6 and 24 h after exercise. In whole muscle, full‐length RyR1 protein content was significantly reduced 6 h (mean (SD); −38 (38)%; P < 0.05) and 24 h post‐SIT (−30 (48)%; P < 0.05) compared to pre‐exercise. Examining each participant's largest response in pooled samples, full‐length RyR1 protein content was reduced in type II (−26 (30)%; P < 0.05) but not type I fibres (−11 (40)%; P > 0.05). Three hours post‐SIT, there was also a decrease in sarco(endo)plasmic reticulum Ca2+ ATPase 1 in type II fibres (−23 (17)%; P < 0.05) and sarco(endo)plasmic reticulum Ca2+ ATPase 2a in type I fibres (−19 (21)%; P < 0.05), despite no time effect for either protein in whole muscle samples (P > 0.05). PGC1A mRNA content was elevated 3 and 6 h post‐SIT (5.3‐ and 3.7‐fold change from pre, respectively; P < 0.05 for both), but peak PGC1A mRNA expression was not significantly correlated with peak RyR1 fragmentation (r2 = 0.10; P > 0.05). In summary, altered Ca2+‐handling protein expression, which occurs primarily in type II muscle fibres, may influence signals for mitochondrial biogenesis as early as 3–6 h post‐SIT in humans.
Key points
Sprint interval training (SIT) has been shown to cause fragmentation of the sarcoplasmic reticulum calcium‐release channel, ryanodine receptor 1 (RyR1), 24 h post‐exercise, which may act as a signal for mitochondrial biogenesis.
In this study, the time course was examined of RyR1 fragmentation in human whole muscle and pooled type I and type II skeletal muscle fibres following a single session of SIT.
Full‐length RyR1 protein content was significantly lower than pre‐exercise by 6 h post‐SIT in whole muscle, and fragmentation was detectable in type II but not type I fibres, though to a lesser extent than in whole muscle.
The peak in PGC1A mRNA expression occurred earlier than RyR1 fragmentation.
The increased temporal resolution and fibre type‐specific responses for RyR1 fragmentation provide insights into its importance to mitochondrial biogenesis in humans.
figure legend Western blotting was performed on whole muscle and pooled type I and II muscle fibre preparations derived from human vastus lateralis muscle biopsy samples collected before and after a single session of sprint interval training (SIT). Full‐length ryanodine receptor 1 (RyR1) protein content was reduced 6 and 24 h post‐exercise in whole muscle samples compared to baseline, despite a heterogeneous time course among individuals. This RyR1 fragmentation proceeded and outlasted the increase in peroxisome proliferator‐activated γ receptor coactivator 1α (PGC1A) mRNA expression. When examining the time point of each individual's peak response, RyR1 fragmentation was evident in type II, but not type I, muscle fibres. These findings suggest that, in humans, mitochondrial biogenesis could be influenced by RyR1 fragmentation 3–6 h post‐SIT in a fibre type‐dependent manner. Created with BioRender.com.
Loading of skeletal muscle changes the tissue phenotype reflecting altered metabolic and functional demands. In humans, heterogeneous adaptation to loading complicates the identification of the ...underpinning molecular regulators. A within-person differential loading and analysis strategy reduces heterogeneity for changes in muscle mass by ∼40% and uses a genome-wide transcriptome method that models each mRNA from coding exons and 3′ and 5′ untranslated regions (UTRs). Our strategy detects ∼3–4 times more regulated genes than similarly sized studies, including substantial UTR-selective regulation undetected by other methods. We discover a core of 141 genes correlated to muscle growth, which we validate from newly analyzed independent samples (n = 100). Further validating these identified genes via RNAi in primary muscle cells, we demonstrate that members of the core genes were regulators of protein synthesis. Using proteome-constrained networks and pathway analysis reveals notable relationships with the molecular characteristics of human muscle aging and insulin sensitivity, as well as potential drug therapies.
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•Muscle loading and unloading regulate the untranslated regions of mRNA•Regulated genes form functional networks central to muscle plasticity•141 genes correlate with muscle growth in 3 independent validation cohorts•Several growth-correlated network genes directly regulate myocyte protein synthesis
Stokes et al. identify and validate a core set of genes that are regulated in proportion to the magnitude of muscle protein turnover with loading. Several of these genes correlate with muscle growth only at their 3′ or 5′ untranslated region, and a subset directly influences protein synthesis in vitro.
Protein ingestion and the ensuing hyperaminoacidemia stimulates skeletal muscle protein synthesis in the postexercise period. This response facilitates muscle remodeling, which is important during ...intensified training. The aim of this study was to determine whether supplementation with α-lactalbumin (LA), with high leucine and tryptophan contents, would improve responses to short periods of intensified aerobic training compared with supplementation with an isonitrogenous quantity of collagen peptides (CP).
Endurance-trained participants (5 male, 6 female, 24 ± 4 yr, V˙O2 = 53.2 ± 9.1 mL·kg·min, peak power output = 320 ± 48 W; means ± SD) consumed a controlled diet (1.0 g·kg·d protein) and refrained from habitual training for 11 d while taking part in this double-blind randomized, crossover trial. The two intervention phases, which consisted of brief intensified training (4 × 4-min cycling intervals at 70% of peak power output on 3 consecutive days) combined with the ingestion of LA or CP supplements after exercise (20 g) and before sleep (40 g), were separated by 4 d of washout without protein supplementation (i.e., the control phase). In response to each phase, myofibrillar (MyoPS), sarcoplasmic protein synthesis (SarcPS) rates (via H2O ingestion) and parameters of sleep quality were measured.
LA ingestion increased plasma leucine (P < 0.001) and tryptophan concentrations (P < 0.001) relative to CP. Intensified training increased MyoPS and SarcPS above the washout phase in LA- and CP-supplemented phases (P < 0.01), with increases being 13% ± 5% and 5% ± 7% greater with LA than CP for MyoPS (P < 0.01) and SarcPS, respectively (P < 0.01).
Despite an isonitrogenous diet, protein synthesis was enhanced to a greater extent when trained participants consumed LA compared with CP during intensified aerobic training, suggesting that protein quality is an important consideration for endurance-trained athletes aiming to augment adaption to exercise training.
Critical torque (CT) represents the highest oxidative steady state for intermittent knee extensor exercise, but the extent to which it is influenced by skeletal muscle mitochondria and sex is ...unclear. Vastus lateralis muscle biopsy samples were collected from 12 females and 12 males –matched for relative maximal oxygen uptake normalized to fat‐free mass (FFM) (F: 57.3 (7.5) ml (kg FFM)−1 min−1; M: 56.8 (7.6) ml (kg FFM)−1 min−1; P = 0.856) – prior to CT determination and performance fatiguability trials. Males had a lower proportion of myosin heavy chain (MHC) I isoform (40.6 (18.4)%) compared to females (59.5 (18.9)%; P = 0.021), but MHC IIa and IIx isoform distributions and protein markers of mitochondrial content were not different between sexes (P > 0.05). When normalized to maximum voluntary contraction (MVC), the relative CT (F: 42.9 (8.3)%; M: 37.9 (9.0)%; P = 0.172) and curvature constant, W′ (F: 26.6 (11.0) N m s (N m)−1; M: 26.4 (6.5) N m s (N m)−1; P = 0.962) were not significantly different between sexes. All protein biomarkers of skeletal muscle mitochondrial content, as well as the proportion of MHC I isoform, positively correlated with relative CT (0.48 < r < 0.70; P < 0.05), and the proportion of MHC IIx isoform correlated positively with relative W′ (r = 0.57; P = 0.007). Indices of performance fatiguability were not different between males and females for MVC‐ and CT‐controlled trials (P > 0.05). Greater mitochondrial protein abundance was associated with attenuated declines in potentiated twitch torque for exercise at 60% MVC (P < 0.05); however, the influence of mitochondrial protein abundance on performance fatiguability was reduced when exercise was prescribed relative to CT. Whether these findings translate to whole‐body exercise requires additional research.
Key points
The quadriceps critical torque represents the highest intensity of intermittent knee extensor exercise for which an oxidative steady state is attainable, but its relationship with skeletal muscle mitochondrial protein abundance is unknown.
Matching males and females for maximal oxygen uptake relative to fat‐free mass facilitates investigations of sex differences in exercise physiology, but studies that have compared critical torque and performance fatiguability during intermittent knee extensor exercise have not ensured equal aerobic fitness between sexes.
Skeletal muscle mitochondrial protein abundance was correlated with critical torque and fatigue resistance for exercise prescribed relative to maximum voluntary contraction but not for exercise performed relative to the critical torque.
Differences between sexes in critical torque, skeletal muscle mitochondrial protein abundance and performance fatiguability were not statistically significant.
Our results suggest that skeletal muscle mitochondrial protein abundance may contribute to fatigue resistance by influencing the critical intensity of exercise.
figure legend Critical torque (CT), performance fatiguability, and skeletal muscle mitochondrial protein content and fibre type were determined for males (M) and females (F) matched for peak oxygen uptake (V̇O2peak${\dot{V}}_{{\mathrm{O}}_{2}\mathrm{peak}}$) per fat‐free mass. The CT and mitochondrial protein content were not significantly different between sexes. Mitochondrial protein content correlated with CT but not the curvature constant, W′. Mitochondrial protein content correlated with fatiguability when intermittent, isometric knee extensor exercise was performed to task failure at 60% MVC but not when it was performed for 30 min 10% below CT.
Abstract Respiratory syncytial virus (RSV) belongs to the family Paramyxoviridae and is the single most important cause of serious lower respiratory tract infections in young children, yet no highly ...effective treatment or vaccine is available. To clarify the potential for an anti-G mAb, 131-2G which has both anti-viral and anti-inflammatory effects, to effectively treat RSV disease, we determined the kinetics of its effect compared to the effect of the anti-F mAb, 143-6C on disease in mice. Treatment administered three days after RSV rA2-line19F (r19F) infection showed 131-2G decreased breathing effort, pulmonary mucin levels, weight loss, and pulmonary inflammation earlier and more effectively than treatment with mAb 143-6C. Both mAbs stopped lung virus replication at day 5 post-infection. These data show that, in mice, anti-G protein mAb is superior to treating disease during RSV infection than an anti-F protein mAb similar to Palivizumab. This combination of anti-viral and anti-inflammatory activity makes 131-2G a promising candidate for treating for active human RSV infection.
Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. In the ...present study, we investigated the effect of prophylactic treatment with the intact and F(ab')2 forms of an anti-G protein monoclonal antibody (MAb), 131-2G, on the humoral and cellular adaptive immune responses to RSV rA2-line19F (r19F) challenge in BALB/c mice. The F(ab')2 form of 131-2G does not decrease virus replication, but intact 131-2G does. The serum specimens for antibodies and spleen cells for memory T cell responses to RSV antigens were analyzed at 30, 45, 75, and 95 days postinfection (p.i.) with or without prior treatment with 131-2G. The ratios of Th2 to Th1 antibody isotypes at each time p.i indicated that both forms of MAb 131-2G shifted the subclass response from a Th2 (IgG1 and IgG2b) to a Th1 (IgG2A) bias. The ratio of IgG1 to IgG2A antibody titer was 3-fold to 10-fold higher for untreated than MAb-treated mice. There was also some increase in IgG (22% ± 13% increase) and neutralization (32% increase) in antibodies with MAb 131-2G prophylaxis at 75 days p.i. Treatment with 131-2G significantly (P ≤ 0.001) decreased the percentage of interleukin-4 (IL-4)-positive CD4 and CD8 cells in RSV-stimulated spleen cells at all times p.i., while the percentage of interferon gamma (IFN-γ) T cells significantly (P ≤ 0.001) increased ≥ 75 days p.i. The shift from a Th2- to a Th1-biased T cell response in treated compared to untreated mice likely was directed by the much higher levels of T-box transcription factor (T-bet) (≥ 45% versus <10%) in CD4 and CD8 T cells and lower levels of Gata-3 (≤ 2% versus ≥ 6%) in CD4 T cells in peptide-stimulated, day 75 p.i. spleen cells. These data show that the RSV G protein affects both humoral and cellular adaptive immune responses, and induction of 131-2G-like antibodies might improve the safety and long-term efficacy of an RSV vaccine.
The data in this report suggest that the RSV G protein not only contributes to disease but also dampens the host immune response to infection. Both effects of G likely contribute to difficulties in achieving an effective vaccine. The ability of MAb 131-2G to block these effects of G suggests that inducing antibodies similar to 131-2G should prevent disease and enhance the adaptive immune response with later RSV infection. The fact that 131-2G binds to the 13-amino-acid region conserved among all strains and that flanking sequences are conserved within group A or group B strains simplifies the task of developing a vaccine to induce 131-2G-like antibodies. If our findings in mice apply to humans, then including the 131-2G binding region of G in a vaccine should improve its safety and efficacy.
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