Mitigating skeletal muscle wasting in unloading and augmenting subsequent recovery.

Skeletal muscle wasting is the hallmark pathophysiological adaptation to unloading or disuse that demonstrates the dependency on frequent mechanical stimulation (e.g. muscle activation and subsequent loading) for homeostasis of normally load-bearing muscles. In the absence of mitigation strategies, no mammalian organism is resistant to muscle atrophy driven by unloading. Given the profound impact of unloading-induced muscle wasting on physical capacity, metabolic health and immune function; mitigation strategies during unloading and/or augmentation approaches during recovery have broad healthcare implications in settings of bed-bound hospitalization, cast immobilization and spaceflight. This topical review aims to: (1) provide a succinct, state-of-the-field summary of seminal and recent findings regarding the mechanisms of unloading-induced skeletal muscle wasting; (2) discuss unsuccessful vs. promising mitigation and recovery augmentation strategies; and (3) identify knowledge gaps ripe for future research. We focus on the rapid muscle atrophy driven by relatively short-term mechanical unloading/disuse, which is in many ways mechanistically distinct from both hypermetabolic muscle wasting and denervation-induced muscle atrophy. By restricting this discussion to mechanical unloading during which all components of the nervous system remain intact (e.g. without denervation models), mechanical loading requiring motor and sensory neural circuits in muscle remain viable targets for both mitigation and recovery augmentation. We emphasize findings in humans with comparative discussions of studies in rodents which enable elaboration of key mechanisms. We also discuss what is currently known about the effects of age and sex as biological factors, and both are highlighted as knowledge gaps and novel future directions due to limited research.

Assessing the impact of boldine on the gastrocnemius using multiomics profiling at 7 and 28 days post-complete spinal cord injury in young male mice.

Spinal cord injury (SCI) results in rapid muscle loss. Exogenous molecular interventions to slow muscle atrophy after SCI have been relatively ineffective and require the search for novel therapeutic targets. Connexin hemichannels (CxHCs) allow nonselective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising preclinical results in slowing atrophy during sepsis and restoring muscle function in dysferlinopathy. We administered 50 mg/kg/day of boldine to spinal cord transected mice beginning 3 days post-injury. Tissue was collected 7 and 28 days post-SCI and the gastrocnemius was used for multiomics profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of the amino acids proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 days post-SCI. SCI resulted in the differential expression of ∼7,700 and ∼2,000 genes at 7 and 28 days, respectively, compared with Sham controls. Pathway enrichment of these genes highlighted ribosome biogenesis at 7 days and translation and oxidative phosphorylation at both timepoints. Boldine altered the expression of ∼150 genes at 7 days and ∼110 genes at 28 days post-SCI. Pathway enrichment of these genes indicated a potential role for boldine in suppressing protein ubiquitination and degradation at the 7-day timepoint. Methylation analyses showed minimal differences between groups. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it attenuated some SCI-induced changes across the metabolome and transcriptome.NEW & NOTEWORTHY This is the first study to describe the multiome of skeletal muscle paralyzed by a spinal cord injury (SCI) in mice across the acute and subacute timeframe after injury. We show large-scale changes in the metabolome and transcriptome at 7 days post-injury compared with 28 days. Furthermore, we show that the alkaloid boldine was able to prevent SCI-induced changes in muscle glucose and free amino acid levels at 7 days, but not 28 days, after SCI.

Dynamic transcriptomic responses to divergent acute exercise stimuli in young adults.

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n = 21, 12 M/9 F, 22 ± 3 yr) or HITT (n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress.NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

Effect of periodontal phenotype characteristics on post-extraction dimensional changes of the alveolar ridge: A prospective case series.

AIM: This study was primarily aimed at assessing the effect that specific periodontal phenotypical characteristics have on alveolar ridge remodelling after tooth extraction. MATERIALS AND METHODS: Patients in need of extraction of a non-molar maxillary tooth were enrolled. Baseline phenotypical characteristics (i.e., mid-facial and mid-palatal soft tissue and bone thickness, and supracrestal soft tissue height [STH]) were recorded upon extraction. A set of clinical, digital imaging (linear and volumetric), and patient-reported outcomes were assessed over a 14-week healing period. RESULTS: A total of 78 subjects were screened. Forty-two subjects completed the study. Linear and volumetric bone changes, as well as vertical linear soft tissue and alveolar ridge volume (soft tissue contour) variations, were indicative of a marked dimensional reduction of the alveolar ridge over time. Horizontal facial and palatal soft tissue thickness gain was observed. Thin facial bone (≤1 mm) upon extraction, compared with thick facial bone (>1 mm), was associated with greater linear horizontal (-4.57 ± 2.31 mm vs. -2.17 ± 1.65 mm, p = .003) and vertical mid-facial (-0.95 ± 0.67 mm vs. -4.08 ± 3.52 mm, p < 0.001) and mid-palatal (-2.03 ± 2.08 mm vs. -1.12 ± 0.99 mm, p = 0.027) bone loss, as well as greater total (-34% ± 10% vs. 15% ± 6%, p < 0.001), facial (-51% ± 19% vs. 28% ± 18%, p = 0.040), and palatal bone volume reduction (-26% ± 14% vs. -8% ± 10%, p < 0.001). Aside from alveolar bone thickness, STH was also found to be a predictor of alveolar ridge resorption since this variable was directly correlated with bone volume reduction. Patient-reported discomfort scores progressively decreased over time, and the mean satisfaction upon study completion was 94.5 ± 0.83 out of 100. CONCLUSIONS: Alveolar ridge remodelling is a physiological phenomenon that occurs after tooth extraction. Post-extraction alveolar ridge atrophy is more marked on the facio-coronal aspect. These dimensional changes are more pronounced in sites exhibiting a thin facial bone phenotype (Clinicaltrials.gov NCT02668289).

Similar Responses in the Akt/Protein Kinase B Signaling Pathway Following Different Lower-Body Exercise Volumes in Recreationally Active Men.

ABSTRACT: Pearson, JR, Moodie, N, Stout, KW, Hawkins, WC, Matuszek, M, Graham, ZA, Siedlik, JA, Vardiman, JP, and Gallagher, PM. Similar responses in the Akt/protein kinase B (PKB) signaling pathway after different lower-body exercise volumes in recreationally active men. J Strength Cond Res 37(5): 1034-1041, 2023-This project examined the differences between a single set (SS) compared to multiple sets (MS) of resistance exercise on the Akt/protein kinase B (PKB) signaling pathway, the expression of insulin-like growth factor-1 ( IGF-1 ), and the receptor for IGF -1 ( IGF-1R ) to better understand the types of resistance training protocols that are most beneficial in stimulating the muscle hypertrophic response. Sixteen healthy men were randomly selected into 2 groups of 8. Subjects in each group received 3 biopsies: (a) before exercise, (b) 15 minutes postexercise, and (c) 180 minutes postexercise. Subjects in the SS group performed 1 set of leg press to failure at 80% of their predetermined 1 repetition maximum (1RM). Subjects in the MS group performed 2 sets of 10 repetitions and 1 set to failure at 80% of their predetermined 1RM, with 3 minutes of rest between each set. Our results indicated no group × time interactions in the concentration of Akt signaling proteins. Furthermore, there were no group × time interactions in IGF-1 or IGF-1R expression. However, phosphorylated 4E-binding protein 1 levels increased 150% from pre to 180 minutes post ( p = 0.005). In addition, there was a significantly greater increase in IGF-1R expression in the SS group compared with the MS group (7.99 ± 10.07 vs. 4.41 ± 6.28; p = 0.026). Collectively, we found that a SS of resistance training evokes a similar acute Akt/PKB pathway response as MS in recreationally active men.

Muscle transcriptomic circuits linked to periarticular physiology in end-stage osteoarthritis.

The ability of individuals with end-stage osteoarthritis (OA) to functionally recover from total joint arthroplasty is highly inconsistent. The molecular mechanisms driving this heterogeneity have yet to be elucidated. Furthermore, OA disproportionately impacts females, suggesting a need for identifying female-specific therapeutic targets. We profiled the skeletal muscle transcriptome in females with end-stage OA (n = 20) undergoing total knee or hip arthroplasty using RNA-Seq. Single-gene differential expression (DE) analyses tested for DE genes between skeletal muscle overlaying the surgical (SX) joint and muscle from the contralateral (CTRL) leg. Network analyses were performed using Pathway-Level Information ExtractoR (PLIER) to summarize genes into latent variables (LVs), i.e., gene circuits, and link them to biological pathways. LV differences in SX versus CTRL muscle and across sources of muscle tissue (vastus medialis, vastus lateralis, or tensor fascia latae) were determined with ANOVA. Linear models tested for associations between LVs and muscle phenotype on the SX side (inflammation, function, and integrity). DE analysis revealed 360 DE genes (|Log2 fold-difference| ≥ 1, FDR ≤ 0.05) between the SX and CTRL limbs, many associated with inflammation and lipid metabolism. PLIER analyses revealed circuits associated with protein degradation and fibro-adipogenic cell gene expression. Muscle inflammation and function were linked to an LV associated with endothelial cell gene expression highlighting a potential regulatory role of endothelial cells within skeletal muscle. These findings may provide insight into potential therapeutic targets to improve OA rehabilitation before and/or following total joint replacement.

Notch, Numb and Numb-like responses to exercise-induced muscle damage in human skeletal muscle.

NEW FINDINGS: What is the central question of this study? Do Notch, Numb and Numb-like expression change in human skeletal muscle after exercise-induced muscle damage? What are the main finding and its importance? Notch gene expression trends toward an increase in response to an acute bout of exercise-induced muscle damage, while Numb and Numb-like expression does not change. These results suggest that human skeletal muscle response to exercise-induced muscle damage is dynamic and may differ from Drosophila and rodent models. Furthermore, the timing of muscle biopsies, training status and muscle damage protocols should be considered. ABSTRACT: This investigation examined changes in the gene and protein expression of Notch, Numb and Numb-like (Numbl) in human skeletal muscle after an acute bout of eccentric exercise-induced muscle damage. Twelve recreationally active male subjects participated in this study. These individuals completed seven sets of 10 repetitions of eccentric leg extension at 120% of one-repetition max with 2 min of rest period between sets. Four muscle biopsies of the vastus lateralis were collected: before exercise (Pre), and 3 h, 2 days and 5 days post-muscle damage. Biopsy samples were used to probe Notch, Numb and Numbl utilizing western blot and RT-qPCR techniques. The results were analysed using a one-way repeated-measures ANOVA. Notch1 mRNA expression trended toward a significant increase from Pre to 2 days post-muscle damage from baseline measures (P = 0.087), while Numb (P = 0.804) and Numbl (P = 0.480) expression was unaltered post-muscle damage. There were no significant differences in protein expression post-muscle damage for any of the proteins. These results suggest that exercise-induced muscle damage, via eccentric exercise, slightly elevates Notch1 mRNA expression.

Mechanisms of exercise as a preventative measure to muscle wasting.

Skeletal muscle is the most abundant tissue in healthy individuals and it has important roles in health beyond voluntary movement. The overall mass and energy requirements of skeletal muscle require it to be metabolically active and flexible to multiple energy substrates. The tissue has evolved to be largely load dependent and it readily adapts in a number of positive ways to repetitive overload, such as various forms of exercise training. However, unloading from extended bed rest and/or metabolic derangements in response to trauma, acute illness, or severe pathology, commonly results in rapid muscle wasting. Decline in muscle mass contributes to multimorbidity, reduces function, and exerts a substantial, negative impact on the quality of life. The principal mechanisms controlling muscle mass have been well described and these cellular processes are intricately regulated by exercise. Accordingly, exercise has shown great promise and efficacy in preventing or slowing muscle wasting through changes in molecular physiology, organelle function, cell signaling pathways, and epigenetic regulation. In this review, we focus on the role of exercise in altering the molecular landscape of skeletal muscle in a manner that improves or maintains its health and function in the presence of unloading or disease.epigenetics; exercise; muscle wasting; resistance training; skeletal muscle.

Locomotor training with adjuvant testosterone preserves cancellous bone and promotes muscle plasticity in male rats after severe spinal cord injury.

Loading and testosterone may influence musculoskeletal recovery after spinal cord injury (SCI). Our objectives were to determine (a) the acute effects of bodyweight-supported treadmill training (TM) on hindlimb cancellous bone microstructure and muscle mass in adult rats after severe contusion SCI and (b) whether longer-term TM with adjuvant testosterone enanthate (TE) delivers musculoskeletal benefit. In Study 1, TM (40 min/day, 5 days/week, beginning 1 week postsurgery) did not prevent SCI-induced hindlimb cancellous bone loss after 3 weeks. In Study 2, TM did not attenuate SCI-induced plantar flexor muscles atrophy nor improve locomotor recovery after 4 weeks. In our main study, SCI produced extensive distal femur and proximal tibia cancellous bone deficits, a deleterious slow-to-fast fiber-type transition in soleus, lower muscle fiber cross-sectional area (fCSA), impaired muscle force production, and levator ani/bulbocavernosus (LABC) muscle atrophy after 8 weeks. TE alone (7.0 mg/week) suppressed bone resorption, attenuated cancellous bone loss, constrained the soleus fiber-type transition, and prevented LABC atrophy. In comparison, TE+TM concomitantly suppressed bone resorption and stimulated bone formation after SCI, produced near-complete cancellous bone preservation, prevented the soleus fiber-type transition, attenuated soleus fCSA atrophy, maintained soleus force production, and increased LABC mass. 75% of SCI+TE+TM animals recovered voluntary over-ground hindlimb stepping, while no SCI and only 20% of SCI+TE animals regained stepping ability. Positive associations between testosterone and locomotor function suggest that TE influenced locomotor recovery. In conclusion, short-term TM alone did not improve bone, muscle, or locomotor recovery in adult rats after severe SCI, while longer-term TE+TM provided more comprehensive musculoskeletal benefit than TE alone.

Mitochondrial health and muscle plasticity after spinal cord injury.

Mitochondria are responsible for aerobic respiration and large-scale ATP production in almost all cells of the body. Their function is decreased in many neurodegenerative and cardiovascular disease states, in metabolic disorders such as type II diabetes and obesity, and as a normal component of aging. Disuse of skeletal muscle from immobilization or unloading triggers alterations of mitochondrial density and activity. Resultant mitochondrial dysfunction after paralysis, which precedes muscle atrophy, may augment subsequent release of reactive oxygen species leading to protein ubiquitination and degradation. Spinal cord injury is a unique form of disuse atrophy as there is a complete or partial disruption in tonic communication between the central nervous system (CNS) and skeletal muscle. Paralysis, unloading and disruption of CNS communication result in a rapid decline in skeletal muscle function and metabolic status with disruption in activity of peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha and calcineurin, key regulators of mitochondrial health and function. External interventions, both acute and chronical with training using body-weight-assisted treadmill training or electrical stimulation have consistently demonstrated adaptations in skeletal muscle mitochondria, and expression of the genes and proteins required for mitochondrial oxidation of fats and carbohydrates to ATP, water, and carbon dioxide. The purpose of this mini-review is to highlight our current understanding as to how paralysis mechanistically triggers downstream regulation in mitochondrial density and activity and to discuss how mitochondrial dysfunction may contribute to skeletal muscle atrophy.

Alterations in mitochondrial fission, fusion, and mitophagic protein expression in the gastrocnemius of mice after a sciatic nerve transection.

INTRODUCTION: Paralysis and unloading of skeletal muscle leads to a rapid loss in muscle size, function and oxidative capacity. The reduction in metabolic capability after disuse leads to dysregulation and increased breakdown of mitochondria by mitophagy. METHODS: Eight-week-old C57BL/6 male mice were given a sham surgery or sciatic nerve transection. Animals were euthanized at 7, 14, 21, or 35 days postsurgery. Whole gastrocnemius muscles were isolated from the animal, weighed and used for Western blotting. RESULTS: Markers of mitochondrial fusion were reduced while fission proteins were elevated following a sciatic nerve transection. There were elevations in phosphorylated unc-51-like kinase 1 (ULK1S555 ) and total expression of Beclin1, and of the mitophagy markers PINK1, p62, and microtubule-associated proteins 1A/1B light chain 3b (LC3-II). CONCLUSIONS: Paralysis of the gastrocnemius leads to a progressive elevation in expression of mitochondrial fission and mitophagic proteins. Rehabilitative or pharmaceutical interventions to limit excess mitophagy may be effective therapies to protect paralyzed muscle mass and function. Muscle Nerve 58: 592-599, 2018.

Plasma adiponectin levels are correlated with body composition, metabolic profiles, and mitochondrial markers in individuals with chronic spinal cord injury.

STUDY DESIGN: Cross-sectional design. OBJECTIVES: This study examined the relationships between circulating adiponectin levels, body composition, metabolic profile, and measures of skeletal muscle mitochondrial enzyme activity and biogenesis. SETTINGS: Clinical Research in a Medical Center. METHODS: Plasma adiponectin was quantified in 19 individuals with chronic spinal cord injury (SCI). Body composition was evaluated by dual x-ray absorptiometry and magnetic resonance imaging. Metabolic profile was assessed by basal metabolic rate (BMR), oxygen uptake (VO2), and intravenous glucose tolerance testing. Mitochondrial enzyme activity of skeletal muscle was obtained by spectrophotometric assays and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and 5' AMP-activated protein kinase (AMPK) protein expression was assessed by Western blots. RESULTS: Adiponectin was negatively related to both total and regional fat mass and positively related to lean mass and muscle mass. Furthermore, there were positive relationships between adiponectin and BMR (r = 0.52, P = 0.02) and VO2 (r = 0.73, P = 0.01). Furthermore, adiponectin was positively related to citrate synthase (r = 0.68, P = 0.002) and complex III activity (r = 0.57, P = 0.02). The relationships between adiponectin and body composition remained significant after accounting for age. The relationships between adiponectin, metabolic profile, and markers of mitochondria mass and activity were influenced by age. CONCLUSIONS: The study demonstrated that adiponectin is closely related to body composition and metabolic profile in persons with SCI and further supports mechanistic studies suggesting that adiponectin may stimulate mitochondrial biogenesis.

Focal adhesion kinase and its role in skeletal muscle.

Skeletal muscle has a remarkable ability to respond to different physical stresses. Loading muscle through exercise, either anaerobic or aerobic, can lead to increases in muscle size and function while, conversely, the absence of muscle loading stimulates rapid decreases in size and function. A principal mediator of this load-induced change is focal adhesion kinase (FAK), a downstream non-receptor tyrosine kinase that translates the cytoskeletal stress and strain signals transmitted across the cytoplasmic membrane by integrins to activate multiple anti-apoptotic and cell growth pathways. Changes in FAK expression and phosphorylation have been found to correlate to specific developmental states in myoblast differentiation, muscle fiber formation and muscle size in response to loading and unloading. With the capability to regulate costamere formation, hypertrophy and glucose metabolism, FAK is a molecule with diverse functions that are important in regulating muscle cell health.

Changes in α7ß1 integrin signaling after eccentric exercise in heat-shocked rat soleus.

INTRODUCTION: α7ß1 integrin links the extracellular matrix to the focal adhesion (FA) in skeletal muscle and serves as a stabilizing and signal relayer. Heat shock (HS) induces expression of proteins that interact with the FA. METHODS: Male Wistar rats were assigned to 1 of 3 groups: control (CON); eccentric exercise (EE); or EE+HS (HS). Soleus muscle was analyzed at 2 h and 48 h post-exercise. RESULTS: The 120-kDa α7 integrin decreased in the EE and HS groups, and the 70-kDa peptide decreased in the EE group at 2 h post-exercise. Total expression of focal adhesion kinase (FAK) and RhoA were decreased in EE and HS at 2 h post-exercise. Expression of phosphorylated FAK(397) decreased in the EE group but not the HS group at 2 h post-exercise. CONCLUSIONS: Long-duration EE may cause alterations in the FA in rat soleus muscle through the α7 integrin subunit and FAK.

Methods comparison: assessing agreement of physiological parameters obtained from exercise on two different cycle ergometers.

The purpose of this study was to determine the agreement of physiological parameters measured during exercise testing on 2 devices at established power outputs (POs). Ten trained male cyclists were recruited. The devices used for comparison were the Lode stationary bicycle ergometer (SBE) (Lode Excalibur) and the PowerTap Pro+ (BPT) (Saris Cycling Group) mobile ergometer. The physiological parameters recorded at established PO (50, 100, 150, 200, 250 W) were heart rate (HR), oxygen consumption ((Equation is included in full-text article.)), pulmonary ventilation (VE), blood lactate, and ratings of perceived exertion (RPE). Subjects were randomized once to the SBE and 3 times to a bicycle equipped with a BPT. After 15 minutes of unloaded pedaling, the trial began with 5 minutes of cycling at 50 W. Intensity increased by 50 W every 5 minutes up to 250 W. Physiological measures were recorded at each PO. Bland-Altman plots were constructed including computation of the ratio of half the range of limits of agreement and the mean of the pairwise means along with bivariate regression calculations for analysis of the linear association between device measurements. Moderate to good agreement was found for HR with agreement improving as PO increased. Comparisons of (Equation is included in full-text article.)found agreement increased as the PO increased. VE, RPE, and lactate did not consistently provide similar measures across trials. The level of agreement between HR and (Equation is included in full-text article.)when comparing the SBE and BPT suggests that the PowerTap Pro+ is a sufficient tool for estimating PO and associated physiological parameters in the field.

Serum metabolomics signatures after an acute bout of combined traditional or high-intensity tactical training in young males and females.

Exercise is a multipotent stimulus that results in large-scale dynamic changes to the systemic molecular profile. Alternative exercise prescriptions and doses would be expected to result in distinct signatures due to differences in duration and intensity. We tested two novel combined endurance and resistance exercise regimens to better understand how differing prescriptions alter the acute metabolomics response at multiple timepoints up to 24h post-exercise. Serum metabolomics for n=37 untrained individuals was analyzed for participants completing traditional combined exercise [TRAD; n = 20 (11M/9F)] or high-intensity tactical training [HITT; n= 17 (9M/8F)] before exercise (pre), and immediately (h0), 3 and 24 h post-exercise (h3 and h24, respectively). We found minimal metabolites had a group by time interaction (2 with FDR < 0.10; 31 with nominal p < 0.05;), but both stimuli resulted in large-scale within-group changes to the circulating metabolome. TRAD consistently had greater numbers of differentially abundant metabolites (FDR < 0.10) as compared to HITT at h0 (431 vs. 333), h3 (435 vs. 331) and h24 (168 vs. 76). The major metabolite classes altered were related to key energy substrates for both groups at h0 (e.g., glucose, pyruvate) and energy replenishment for h3 and h24 (e.g., 12,13 diHOME, palmitylcarnitine, free fatty acids). In summary, our data are the first to describe the acute changes in the circulating metabolome following combined endurance and resistance exercise. Additionally, we show the two distinct doses of combined exercise led to generally similar patterns of responses, with the longer duration TRAD dose resulting in a higher magnitude of change.

Differentially expressed heterogeneous overdispersion genes testing for count data.

The mRNA-seq data analysis is a powerful technology for inferring information from biological systems of interest. Specifically, the sequenced RNA fragments are aligned with genomic reference sequences, and we count the number of sequence fragments corresponding to each gene for each condition. A gene is identified as differentially expressed (DE) if the difference in its count numbers between conditions is statistically significant. Several statistical analysis methods have been developed to detect DE genes based on RNA-seq data. However, the existing methods could suffer decreasing power to identify DE genes arising from overdispersion and limited sample size, where overdispersion refers to the empirical phenomenon that the variance of read counts is larger than the mean of read counts. We propose a new differential expression analysis procedure: heterogeneous overdispersion genes testing (DEHOGT) based on heterogeneous overdispersion modeling and a post-hoc inference procedure. DEHOGT integrates sample information from all conditions and provides a more flexible and adaptive overdispersion modeling for the RNA-seq read count. DEHOGT adopts a gene-wise estimation scheme to enhance the detection power of differentially expressed genes when the number of replicates is limited as long as the number of conditions is large. DEHOGT is tested on the synthetic RNA-seq read count data and outperforms two popular existing methods, DESeq2 and EdgeR, in detecting DE genes. We apply the proposed method to a test dataset using RNAseq data from microglial cells. DEHOGT tends to detect more differently expressed genes potentially related to microglial cells under different stress hormones treatments.

Muscle-derived microRNAs correlated with thigh lean mass gains during progressive resistance training in older adults.

Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared with younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNAs (miRNAs) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11 M/7 F, 66 ± 1 yr) who underwent three times per wk RT for 30 wk [e.g., high intensity three times/wk (HHH, n = 9) or alternating high-low-high (HLH) intensity (n = 9)], after a standardized 4-wk washin. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using weighted gene correlation network analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change [as measured by dual-energy X-ray absorptiometry (DXA)]. Although no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT to maximize skeletal muscle mass accrual in older adults.NEW & NOTEWORTHY In this work, we identified a set of microRNAs correlated with thigh lean mass gains in a group of older adults. To our knowledge, this is the first time these microRNAs have been identified as novel predictive biomarkers correlating with lean mass gains in aging adults. As biomarkers, these may help interventionalists identify older individuals that are positively responding to an exercise intervention.

Pharmacology of boldine: summary of the field and update on recent advances.

Over the past decade, boldine, a naturally occurring alkaloid found in several plant species including the Chilean Boldo tree, has garnered attention for its efficacy in rodent models of human disease. Some of the properties that have been attributed to boldine include antioxidant activities, neuroprotective and analgesic actions, hepatoprotective effects, anti-inflammatory actions, cardioprotective effects and anticancer potential. Compelling data now indicates that boldine blocks connexin (Cx) hemichannels (HCs) and that many if not all of its effects in rodent models of injury and disease are due to CxHC blockade. Here we provide an overview of boldine's pharmacological properties, including its efficacy in rodent models of common human injuries and diseases, and of its absorption, distribution, pharmacokinetics, and metabolism.

Boldine Alters Serum Lipidomic Signatures after Acute Spinal Cord Transection in Male Mice.

Traumatic spinal cord injury (SCI) results in wide-ranging cellular and systemic dysfunction in the acute and chronic time frames after the injury. Chronic SCI has well-described secondary medical consequences while acute SCI has unique metabolic challenges as a result of physical trauma, in-patient recovery and other post-operative outcomes. Here, we used high resolution mass spectrometry approaches to describe the circulating lipidomic and metabolomic signatures using blood serum from mice 7 d after a complete SCI. Additionally, we probed whether the aporphine alkaloid, boldine, was able to prevent SCI-induced changes observed using these 'omics platforms'. We found that SCI resulted in large-scale changes to the circulating lipidome but minimal changes in the metabolome, with boldine able to reverse or attenuate SCI-induced changes in the abundance of 50 lipids. Multiomic integration using xMWAS demonstrated unique network structures and community memberships across the groups.