Editor’s Choice Articles

Maintenance of skeletal muscle mass and function is critical to health and wellbeing throughout the lifespan. However, disuse through reduced physical activity (e.g., sedentarism), immobilisation, bed rest or microgravity has significant adverse effects on skeletal muscle health. Conversely, resistance exercise training (RET) induces positive muscle mass and strength adaptations. Several studies have employed microarray technology to understand the transcriptional basis of muscle atrophy and hypertrophy after disuse and RET, respectively, to devise fully effective therapeutic interventions. More recently, rapidly falling costs have seen RNA-sequencing (RNA-seq) increasingly applied in exploring muscle adaptations to RET and disuse. The aim of this review is to summarise the transcriptional responses to RET or disuse measured via RNA-seq in young and older adults. We also highlight analytical considerations to maximise the utility of RNA-seq in the context of skeletal muscle research. The limited number of muscle transcriptional signatures obtained thus far with RNA-seq are generally consistent with those obtained with microarrays. However, RNA-seq may provide additional molecular insight, particularly when combined with data-driven approaches such as correlation network analyses. In this context, it is essential to consider the most appropriate study design parameters as well as bioinformatic and statistical approaches. This will facilitate the use of RNA-seq to better understand the transcriptional regulators of skeletal muscle plasticity in response to increased or decreased use. Full article

(1) Background: Maximal fat oxidation (MFO), its associated exercise intensity (Fatmax) and the cross-over point (COP) are known indirect calorimetry-based diagnostics for whole-body metabolic health and exercise. However, large inter- and intra-individual variability in determining their corresponding intensity makes their use inconsistent, whether the intensity is based on power output or oxygen uptake. Blood lactate concentration (BLC) has often reflected a range in MFO and COP, which may offer another non-indirect calorimetry dimension based on the near equilibrium between lactate and pyruvate at the molecular level, which biochemically determines an interchange between lactate and relative rate of carbohydrate (relCHO) and relative rate of fat utilization (relFAO). This paper proposes a new testing approach describing relCHO as a function of BLC, with an individualized half-maximal activation constant of relCHO (kel), to explain and predict the variability in MFO, Fatmax and COP. (2) Methods: Following ethical approval, twenty-one healthy males participated in the incremental cardiorespiratory maximal test, and capillary BLC was measured. Indirect calorimetry relCHO and relFAO were calculated, and a constant kel that reflected 50% of CHO saturation level was estimated as a sigmoid function of BLC (mmol·L⁻¹): relCHO = 100/(1 + kel/BLC²). (3) Results: 86% of relCHO variability was explained by BLC levels. The individualized kel estimations, which were 1.82 ± 0.95 (min/max 0.54/4.4) (mmol·L⁻¹)² independently explained 55% MFO and 44% of COP variabilities. Multiple regression analysis resulted in kel as the highest independent predictor of Fatmax (adjusted r-square = 22.3%, p < 0.05), whilst classic intensity-based predictors (peak power, maximal oxygen uptake, fixed BLC at 4 mmol·L⁻¹) were not significant predictors. (4) Conclusions: The BLC-relCHO model, with its predictor kel explains the inter- and intra-individual variability in MFO, its exercise intensity Fatmax and power outs at COP through dynamic changes in BLC, fat and carbohydrates regardless of the intensity at which exercise takes place. kel capability as a predictor of MFO, Fatmax and COP independently of their associated intensities provides a new diagnostic tool in physiological exercise testing for health and exercise performance. Full article

Limited pre-clinical and clinical data suggest theacrine or theacrine-based supplements modulate biological processes associated with lipid metabolism and aging. Herein, we sought to examine if 12 weeks of daily supplementation with a theacrine-based supplement (termed NAD3^®; 312 mg of combined Wasabia japonica freeze-dried rhizome standardized for isothicyantes, theacrine, and copper (I)niacin chelate) altered serum lipids as well as select nicotinamide adenine dinucleotide (NAD⁺)-associated metabolites in peripheral blood mononuclear cells (PBMCs). Twenty-eight participants (12 males, 16 females) were randomly assigned to receive either NAD3 (n = 13; age: 52 ± 7 years old, body mass index: 29.0 ± 5.0 kg/m²) or a cellulose placebo (n = 15; age: 51 ± 5 years old, body mass index: 28.3 ± 3.9 kg/m²). Blood samples were obtained in mornings following overnight fasts prior to supplementation (Pre) and following the 12-week intervention (Post). PBMCs were freshly isolated and prepared for targeted NAD⁺ metabolomics, and serum as well as whole blood was assayed for blood lipids and other safety markers through a commercial laboratory. Significant interactions (p < 0.05) were observed for total cholesterol, LDL cholesterol, and LDL: HDL ratio and post hoc analyses indicated these biomarkers significantly decreased with NAD3 supplementation (Pre-to-Post percent decreases were 11.1, 15.2, and −18.9%, respectively). A significant interaction was also observed for PBMC NAD⁺: NADH values, where levels trended downward from Pre to Post in the CTL group (p = 0.081) and values at Post were greater in NAD3 versus CTL (p = 0.023). No interactions were observed for systolic/diastolic blood pressure, body mass, or blood markers indicative of clinical safety. Although participant numbers were limited, these first-in-human data demonstrate a theacrine-based NAD3 supplement can favorably alter biomarkers of lipid metabolism and cellular NAD⁺ status. However, the latter data are limited to targeted NAD⁺ metabolites, and the effects of supplementation on other cellular metabolites or mechanisms related to the observed outcomes need to be further explored. Full article