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CARM1 (coactivator associated arginine methyltransferase 1) has recently emerged as a powerful regulator of skeletal muscle biology. However, the molecular mechanisms by which the methyltransferase remodels muscle remain to be fully understood. In this study, carm1 skeletal muscle-specific knockout (mKO) mice exhibited lower muscle mass with dysregulated macroautophagic/autophagic and atrophic signaling, including depressed AMP-activated protein kinase (AMPK) site-specific phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1; Ser555) and FOXO3 (forkhead box O3; Ser588), as well as MTOR (mechanistic target of rapamycin kinase)-induced inhibition of ULK1 (Ser757), along with AKT/protein kinase B site-specific suppression of FOXO1 (Ser256) and FOXO3 (Ser253). In addition to lower mitophagy and autophagy flux in skeletal muscle, carm1 mKO led to increased mitochondrial PRKN/parkin accumulation, which suggests that CARM1 is required for basal mitochondrial turnover and autophagic clearance. carm1 deletion also elicited PPARGC1A (PPARG coactivator 1 alpha) activity and a slower, more oxidative muscle phenotype. As such, these carm1 mKO-evoked adaptations disrupted mitophagy and autophagy induction during food deprivation and collectively served to mitigate fasting-induced muscle atrophy. Furthermore, at the threshold of muscle atrophy during food deprivation experiments in humans, skeletal muscle CARM1 activity decreased similarly to our observations in mice, and was accompanied by site-specific activation of ULK1 (Ser757), highlighting the translational impact of the methyltransferase in human skeletal muscle. Taken together, our results indicate that CARM1 governs mitophagic, autophagic, and atrophic processes fundamental to the maintenance and remodeling of muscle mass. Targeting the enzyme may provide new therapeutic approaches for mitigating skeletal muscle atrophy. Abbreviation: ADMA: asymmetric dimethylarginine; AKT/protein kinase B: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; CARM1: coactivator associated arginine methyltransferase 1; Col: colchicine; CSA: cross-sectional area; CTNS: cystinosin, lysosomal cystine transporter; EDL: extensor digitorum longus; FBXO32/MAFbx: F-box protein 32; FOXO: forkhead box O; GAST: gastrocnemius; H2O2: hydrogen peroxide; IMF: intermyofibrillar; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mKO: skeletal muscle-specific knockout; MMA: monomethylarginine; MTOR: mechanistic target of rapamycin kinase; MYH: myosin heavy chain; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; OXPHOS: oxidative phosphorylation; PABPC1/PABP1: poly(A) binding protein cytoplasmic 1; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PRMT: protein arginine methyltransferase; Sal: saline; SDMA: symmetric dimethylarginine; SIRT1: sirtuin 1; SKP2: S-phase kinase associated protein 2; SMARCC1/BAF155: SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1; SOL: soleus; SQSTM1/p62: sequestosome 1; SS: subsarcolemmal; TA: tibialis anterior; TFAM: transcription factor A, mitochondrial; TFEB: transcription factor EB; TOMM20: translocase of outer mitochondrial membrane 20; TRIM63/MuRF1: tripartite motif containing 63; ULK1: unc-51 like autophagy activating kinase 1; VPS11: VPS11 core subunit of CORVET and HOPS complexes; WT: wild-type. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine if the counting talk test can be used to discern whether an individual is exercising above or at/below maximal lactate steady state. Twenty-two participants completed VO[subscript 2]peak and counting talk test incremental step tests followed by an endurance test at 65% of work rate at VO[subscript 2]peak (WR[subscript VO2peak]). The change in relative count time during endurance exercise decreased in those exercising above maximal lactate steady state only (p < 0.01); however, this change was less than 1 second. Despite a significant correlation during the incremental step test, large changes in counting talk test performance and blood lactate concentration occurred at different points and there was considerable inter-individual variability in counting talk test performance at a given blood lactate concentration. These results suggest that the counting talk test cannot discern whether an individual is exercising above maximal lactate steady state and that it cannot be used to accurately prescribe intensities targeting specific blood lactate concentrations.

We tested the hypothesis that AMPK activation and peroxisome proliferator gamma coactivator 1 alpha (PGC-1α) expression are not augmented as exercise intensity (power output) increases from maximal to supramaximal intensities and conducted an exploratory analysis comparing AMPK activation and PGC-1α expression in males and females. Seventeen (n = 9 males; n = 8 females) recreationally active, healthy, young individuals volunteered to participate in the current study. Participants completed work matched interval exercise at 100% (Max) and 133% (Supra) of peak work rate (WRpeak). Intervals were 1 min in duration and participants were prescribed 6 and 8 intervals of Max and Supra, respectively, to equate external work across protocols. PGC-1α mRNA expression and activation of AMPK (p-ACC) were examined in muscle biopsy samples. Interval WR (watts; W), intensity (%WRpeak) and average HR (bpm), blood lactate (mmol/L) and rating of perceived exertion were all higher (all p < 0.05) in Supra. Fatigue was greater (p < 0.05) in Supra. PGC-1α mRNA expression significantly increased after exercise in Max (p < 0.01) and Supra (p < 0.01), but was not significantly different (p = 0.71) between intensities. A main effect of time (Pre – 0 h) (p < 0.01) was observed for p-ACC; however, no effect of intensity (p = 0.08) or interaction (p = 0.97) was observed. No significant effects of time (p = 0.05) intensity (p = 0.42), or interaction (p = 0.97) were observed for p-AMPK (Thr172). Exploratory sex analysis demonstrated a main effect of sex for p-ACC (greater p-ACC in males; p < 0.05) but not for p-AMPK or PGC-1α expression. Our results confirm that AMPK-PGC-1α signalling is not augmented following supramaximal exercise and provide novel data demonstrating a decrease in AMPK activation (p-ACC) in females compared to men. Trial registration: . [ABSTRACT FROM AUTHOR]

Many reports describe using a supramaximal verification phase—exercising at a power output higher than the highest power output recorded during an incremental cardiopulmonary test—to validate VO2max. The impact of verification phases on estimating the proportion of individuals who increased VO2peak in response to high-intensity interval training (HIIT) remains an underexplored area in the individual response literature. This analysis investigated the influence of same-day and separate-day verification phases during repeated measurements (incremental tests—INCR1 and INCR2; incremental tests + supramaximal verification phases—INCR1+ and INCR2+) of VO2peak on typical error (TE) and the proportion of individuals classified as responders (i.e., the response rate) following 4 weeks of HIIT (n = 25) or a no-exercise control period (n = 9). Incorporation of supramaximal verification consistently reduced the standard deviation of individual response, TE, and confidence interval (CI) widths. However, variances were statistically similar across all groups (p > 0.05). Response rates increased when incorporating either one (INCR1 to INCR1+; 24%–48%, p = 0.07) or two (INCR2 to INCR2+; 28%–48%, p = 0.063) supramaximal verification phases. However, response rates remained unchanged when either zero-based thresholds or smallest worthwhile difference response thresholds were used (50% and 90% CIs, all p > 0.05). Supramaximal verification phases reduced random variability in VO2peak response to HIIT. Compared with separate-day testing (INCR2 and INCR2+), the incorporation of a same-day verification (INCR1+) reduced CI widths the most. Researchers should consider using a same-day verification phase to reduce uncertainty and better estimate VO2peak response rate to HIIT. [ABSTRACT FROM AUTHOR]

Previous studies have concluded that wide variance in changes in insulin sensitivity markers following exercise training demonstrates heterogeneity in individual trainability. However, these studies frequently don't account for technical, biological, and random within-subject measurement error. We used the standard deviation of individual responses (SDIR) to determine whether interindividual variability in trainability exists for fasting and postprandial insulin sensitivity outcomes following low-volume sprint interval training (SIT). We pooled data from 63 untrained participants who completed 6 weeks of SIT (n = 49; VO2max: 35 (7) mL⋅kg−1⋅min−1) or acted as no-intervention controls (n = 14; VO2max: 34 (6) mL⋅kg−1⋅min−1). Fasting and oral glucose tolerance test (OGTT)-derived measures of insulin sensitivity were measured pre- and post-intervention. SDIR values were positive and exceeded a small effect size threshold for changes in fasting glucose (SDIR = 0.27 [95%CI 0.07,0.38] mmol⋅L−1), 2-h OGTT glucose (SDIR = 0.89 [0.22,1.23] mmol⋅L−1), glucose area-under-the-curve (SDIR = 66.4 [−81.5,124.3] mmol⋅L−1⋅120min−1) and The Cederholm Index (SDIR = 7.2 [−16.0,19.0] mg⋅l2⋅mmol−1⋅mU−1⋅min−1), suggesting meaningful individual responses to SIT, whilst SDIR values were negative for fasting insulin, fasting insulin resistance and insulin AUC. For all variables, the 95% CIs were wide and/or crossed zero, highlighting uncertainty about the existence of true interindividual differences in exercise trainability. Only 2–22% of participants could be classified as responders or non-responders with more than 95% certainty. Our findings demonstrate it cannot be assumed that variation in changes in insulin sensitivity following SIT is attributable to inherent differences in trainability, and reiterate the importance of accounting for technical, biological, and random error when examining heterogeneity in health-related training adaptations. Highlights This study tested whether true interindividual variability exists for changes in insulin sensitivity and glyceamic control following 6-weeks of low volume sprint interval training (SIT). The high level of technical, biological, and random error associated with repeated measurements of insulin sensitivity and glycaemic control, means we can neither confidently conclude that there is evidence of true interindividual differences in the trainability of these outcomes following SIT, nor confidently identify responders or non-responders for such parameters. Researchers contrasting responders vs. non-responders for a given parameter, either to understand mechanisms of adaptation and/or develop physiological/genetic/epigenetic predictors of response, need to be aware that identification of responders and non-responders with sufficient certainty may not be achievable for parameters with a high level of technical, biological, and random error. [ABSTRACT FROM AUTHOR]