Adverse Skeletal Muscle Adaptations in Individuals Born Preterm-A Comprehensive Review.

Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and obesity later in life, leading to an increased risk of all-cause mortality in young adults born prematurely. While these preterm-birth-related conditions have been well characterized, less is known about the long-term effects of preterm birth on skeletal muscle health and, specifically, an individual's skeletal muscle hypertrophic potential later in life. In this review, we discuss how a confluence of potentially interrelated and self-perpetuating elements associated with preterm birth might converge on anabolic and catabolic pathways to ultimately blunt skeletal muscle hypertrophy, identifying critical areas for future research.

Vanadium Pentoxide Exposure Causes Strain-Dependent Changes in Mitochondrial DNA Heteroplasmy, Copy Number, and Lesions, but Not Nuclear DNA Lesions.

Interstitial lung diseases (ILDs) are lethal lung diseases characterized by pulmonary inflammation and progressive lung interstitial scarring. We previously developed a mouse model of ILD using vanadium pentoxide (V2O5) and identified several gene candidates on chromosome 4 associated with pulmonary fibrosis. While these data indicated a significant genetic contribution to ILD susceptibility, they did not include any potential associations and interactions with the mitochondrial genome that might influence disease risk. To conduct this pilot work, we selected the two divergent strains we previously categorized as V2O5-resistant C57BL6J (B6) and -responsive DBA/2J (D2) and compared their mitochondrial genome characteristics, including DNA variants, heteroplasmy, lesions, and copy numbers at 14- and 112-days post-exposure. While we did not find changes in the mitochondrial genome at 14 days post-exposure, at 112 days, we found that the responsive D2 strain exhibited significantly fewer mtDNA copies and more lesions than control animals. Alongside these findings, mtDNA heteroplasmy frequency decreased. These data suggest that mice previously shown to exhibit increased susceptibility to pulmonary fibrosis and inflammation sustain damage to the mitochondrial genome that is evident at 112 days post-V2O5 exposure.

NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia.

Approximately 1 in 10 newborns are born preterm and require supplemental oxygen (O2) in an extrauterine environment following birth. Supplemental O2 can induce oxidative stress that can impair mitochondrial function, resulting in lung injury and increased risk in early life pulmonary diseases. The nuclear factor-erythroid 2 related factor 2 (NRF2) protects the cells from oxidative stress by regulating the expression of genes containing antioxidant response elements and many mitochondrial-associated genes. In this study, we compared Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) mice to define the role of NRF2 in lung mitochondrial genomic features in late embryonic development in mice (embryonic days, E13.5 and E18.5) versus birth (postnatal day 0, PND0). We also determined whether NRF2 protects lung mitochondrial genome parameters in postnatal mice exposed to a 72 h hyperoxia environment. We found Nrf2-/- embryonic lungs were characterized by decreases in mtDNA copies from E13.5 to E18.5. Interestingly, Nrf2-/- heteroplasmy frequency was significantly higher than Nrf2+/+ at E18.5, though this effect reversed at PND0. In postnatal mice exposed to hyperoxia, we identified three- to four-fold increases in mitochondria-encoded mitochondrial genes, which regulate oxidative phosphorylation. Overall, our findings demonstrate a potentially critical role of NRF2 in mediating long-term effects of hyperoxia on mitochondrial function.

Military Body Composition Standards and Physical Performance: Historical Perspectives and Future Directions.

ABSTRACT: Harty, PS, Friedl, KE, Nindl, BC, Harry, JR, Vellers, HL, and Tinsley, GM. Military body composition standards and physical performance: historical perspectives and future directions. J Strength Cond Res 36(12): 3551-3561, 2022-US military physique and body composition standards have been formally used for more than 100 years. These metrics promote appropriate physical fitness, trim appearance, and long-term health habits in soldiers, although many specific aspects of these standards have evolved as evidence-based changes have emerged. Body composition variables have been shown to be related to many physical performance outcomes including aerobic capacity, muscular endurance, strength and power production, and specialized occupational tasks involving heavy lifting and load carriage. Although all these attributes are relevant, individuals seeking to improve military performance should consider emphasizing strength, hypertrophy, and power production as primary training goals, as these traits appear vital to success in the new Army Combat Fitness Test introduced in 2020. This fundamental change in physical training may require an adjustment in body composition standards and methods of measurement as physique changes in modern male and female soldiers. Current research in the field of digital anthropometry (i.e., 3-D body scanning) has the potential to dramatically improve performance prediction algorithms and potentially could be used to inform training interventions. Similarly, height-adjusted body composition metrics such as fat-free mass index might serve to identify normal weight personnel with inadequate muscle mass, allowing for effective targeted nutritional and training interventions. This review provides an overview of the origin and evolution of current US military body composition standards in relation to military physical readiness, summarizes current evidence relating body composition parameters to aspects of physical performance, and discusses issues relevant to the emerging modern male and female warrior.

Mitochondrial DNA lesions and copy number are strain dependent in endurance-trained mice.

In this pilot work, we selected two inbred strains that respond well to endurance training (ET) (FVB/NJ, and SJL/J strains), and two strains that respond poorly (BALB/cByJ and NZW/LacJ), to determine the effect of a standardized ET treadmill program on mitochondrial and nuclear DNA (nucDNA) integrity, and mitochondrial DNA (mtDNA) copy number. DNA was isolated from plantaris muscles (n = 37) and a gene-specific quantitative PCR-based assay was used to measure DNA lesions and mtDNA copy number. Mean mtDNA lesions were not different within strains in the sedentary or exercise-trained states. However, mtDNA lesions were significantly higher in trained low-responding NZW/LacJ mice (0.24 ± 0.06 mtDNA lesions/10 Kb) compared to high-responding strains (mtDNA lesions/10 Kb: FVB/NJ = 0.11 ± 0.01, p = .049; SJL/J = 0.04 ± 0.02; p = .003). ET did not alter mean mtDNA copy numbers for any strain, although both sedentary and trained FVB/NJ mice had significantly higher mtDNA copies (99,890 ± 4,884 mtDNA copies) compared to low-responding strains (mtDNA copies: BALB/cByJ = 69,744 ± 4,675; NZW/LacJ = 65,687 ± 5,180; p < .001). ET did not change nucDNA lesions for any strain, however, SJL/J had the lowest mean nucDNA lesions (3.5 ± 0.14 nucDNA lesions/6.5 Kb) compared to all other strains (nucDNA lesions/6.5 Kb: FVB/NJ = 4.4 ± 0.11; BALB/cByJ = 4.7 ± 0.09; NZW/LacJ = 4.4 ± 0.11; p < .0001). Our results demonstrate strain differences in plantaris muscle mtDNA lesions in ET mice and, independent of condition, differences in mean mtDNA copy and nucDNA lesions between strains.

Association between Mitochondrial DNA Sequence Variants and V˙O2 max Trainability.

PURPOSE: We designed the study to determine whether mitochondrial DNA (mtDNA) haplogroup, sequence, and heteroplasmy differed between individuals previously characterized as low (LR) or high responders (HR) as defined by their maximal oxygen uptake response to a standardized aerobic exercise training program. METHODS: DNA was isolated from whole blood in subjects from the HERITAGE Family Study that were determined to be either HR (n = 15) or LR (n = 15). mtDNA was amplified by long-range polymerase chain reaction, then tagged with Nextera libraries and sequenced on a MiSeq instrument. RESULTS: Different mtDNA haplogroup subtypes were found in HR and LR individuals. Compared with HR subjects, significantly more LR subjects had variants in 13 sites, including 7 in hypervariable (HV) regions: HV2 (G185A: 0 vs 6, P = 0.02; G228A: 0 vs 5, P = 0.04; C295T: 0 vs 6; P = 0.04), HV3 (C462T: 0 vs 5, P = 0.04; T489C: 0 vs 5; P = 0.04), and HV1 (C16068T: 0 vs 6, P = 0.02; T16125C: 0 vs 6, P = 0.02). Remaining variants were in protein coding genes, mtND1 (1 vs 8, P = 0.02), mtND3 (A10397G: 0 vs 5, P = 0.04), mtND4 (A11250G: 1 vs 8, P = 0.02), mtND5 (G13707A: 0 vs 5, P = 0.04), and mtCYTB (T14797C: 0 vs 5, P = 0.04; C15451A: 1 vs 8, P = 0.02). Average total numbers of heteroplasmies (P = 0.83) and frequency of heteroplasmies (P = 0.05) were similar between the groups. CONCLUSIONS: Our findings provide specific sites across the mitochondrial genome that may be related to maximal oxygen uptake trainability.

A High Fat/High Sugar Diet Alters the Gastrointestinal Metabolome in a Sex Dependent Manner.

The gut metabolome offers insight for identifying the source of diet related pathology. As such, the purpose of this study was to characterize alterations of the gut metabolome in female and male C57BL/6J mice randomly assigned to a standard "chow" diet (CHOW) or a high fat/high sugar diet (HFHS; 45% fat and 20% fructose drinking solution) for nine weeks. Cecal metabolites were extracted and an untargeted analysis via LC-MS/MS was performed. Partial Least Sums Discriminate Analysis (PLS-DA) presented significant differences between the two diet groups in a sex-dependent manner. Mann-Whitney U-tests revealed 2443 and 1669 features to be significantly different between diet groups in the females and males, respectively. The majority of altered metabolites were depleted within the cecum of the HFHS fed mice. Metabolic pathways associated with galactose metabolism, leukotriene metabolism, and androgen and estrogen biosynthesis and metabolism were differentially altered with an HFHS diet between sexes. We concluded the immense metabolite depletion and elevation of adverse metabolites associated with the HFHS diet is suggestive of poor gut health. Further, the differential alterations between female and male mice suggests that sex plays an important role in determining the effect of diet on the metabolome and host health.

Multi-walled carbon nanotubes upregulate mitochondrial gene expression and trigger mitochondrial dysfunction in primary human bronchial epithelial cells.

Nanomaterials are a relatively new class of materials that acquire novel properties based on their reduced size. While these materials have widespread use in consumer products and industrial applications, the potential health risks associated with exposure to them remain to be fully characterized. Carbon nanotubes are among the most widely used nanomaterials and have high potential for human exposure by inhalation. These nanomaterials are known to penetrate the cell membrane and interact with intracellular molecules, resulting in a multitude of documented effects, including oxidative stress, genotoxicity, impaired metabolism, and apoptosis. While the capacity for carbon nanotubes to damage nuclear DNA has been established, the effect of exposure on mitochondrial DNA (mtDNA) is relatively unexplored. In this study, we investigated the potential of multi-walled carbon nanotubes (MWCNTs) to impair mitochondrial gene expression and function in human bronchial epithelial cells (BECs). Primary BECs were exposed to sub-cytotoxic doses (up to 3 µg/ml) of MWCNTs for 5 d and assessed for changes in expression of all mitochondrial protein-coding genes, heteroplasmies, and insertion/deletion mutations (indels). Exposed cells were also measured for cytotoxicity, metabolic function, mitochondrial abundance, and mitophagy. We found that MWCNTs upregulated mitochondrial gene expression, while significantly decreasing oxygen consumption rate and mitochondrial abundance. Confocal microscopy revealed induction of mitophagy by 2 hours of exposure. Mitochondrial DNA heteroplasmy and insertion/deletion mutations were not significantly affected by any treatment. We conclude that carbon nanotubes cause mitochondrial dysfunction that leads to mitophagy in exposed BECs via a mechanism unrelated to its reported genotoxicity.

Inter-individual variation in adaptations to endurance and resistance exercise training: genetic approaches towards understanding a complex phenotype.

Exercise training which meets the recommendations set by the National Physical Activity Guidelines ensues a multitude of health benefits towards the prevention and treatment of various chronic diseases. However, not all individuals respond well to exercise training. That is, some individuals have no response, while others respond poorly. Genetic background is known to contribute to the inter-individual (human) and -strain (e.g., mice, rats) variation with acute exercise and exercise training, though to date, no specific genetic factors have been identified that explain the differential responses to exercise. In this review, we provide an overview of studies in human and animal models that have shown a significant contribution of genetics in acute exercise and exercise training-induced adaptations with standardized endurance and resistance training regimens, and further describe the genetic approaches which have been used to demonstrate such responses. Finally, our current understanding of the role of genetics and exercise is limited primarily to the nuclear genome, while only a limited focus has been given to a potential role of the mitochondrial genome and its interactions with the nuclear genome to predict the exercise training-induced phenotype(s) responses. We therefore discuss the mitochondrial genome and literature that suggests it may play a significant role, particularly through interactions with the nuclear genome, in the inherent ability to respond to exercise.

Inter-individual variation in health and disease associated with pulmonary infectious agents.

Respiratory infectious diseases resulting from bacterial or viral pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, respiratory syncytial virus (RSV), or influenza, are major global public health concerns. Lower respiratory tract infections are leading causes of morbidity and mortality, only behind ischemic heart disease and stroke (GBD 2015 LRI Collaborators in Lancet Infect Dis 17(11):1133-1161, 2017). Developing countries are particularly impacted by these diseases. However, while many are infected with viruses such as RSV (> 90% of all individuals are infected by age 2), only sub-populations develop severe disease. Many factors may contribute to the inter-individual variation in response to respiratory infections, including gender, age, socioeconomic status, nutrition, and genetic background. Association studies with functional single nucleotide polymorphisms in biologically plausible gene candidates have been performed in human populations to provide insight to the molecular genetic contribution to pulmonary infections and disease severity. In vitro cell models and genome-wide association studies in animal models of genetic susceptibility to respiratory infections have also identified novel candidate susceptibility genes, some of which have also been found to contribute to disease susceptibility in human populations. Genetic background may also contribute to differential efficacy of vaccines against respiratory infections. Development of new genetic mouse models such as the collaborative cross and diversity outbred mice should provide additional insight to the mechanisms of genetic susceptibility to respiratory infections. Continued investigation of susceptibility factors should provide insight to novel strategies to prevent and treat disease that contributes to global morbidity and mortality attributed to respiratory infections.

High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement.

Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s) may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels. Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD) or high fat/high sugar (HFHS) diet for 9-11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males) and 17ß-estradiol (females) to determine if sex hormone augmentation altered diet-induced changes in activity. Results: 117 mice (56♂, 61♀) were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p < 0.0001; female: p < 0.0001) and had significantly higher body fat (male: p < 0.0001; female: p < 0.0001). The HFHS diet did not reduce sex hormone levels, but did significantly reduce acute running-wheel distance in male (p = 0.05, 70 ± 28%) and female mice (p = 0.02, 57 ± 26%). In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat. Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones.

Environmental Endocrine Disruptor Affects Voluntary Physical Activity in Mice.

INTRODUCTION: Voluntary physical activity levels are regulated by sex hormones. The purpose of this study was to determine the effect of the endocrine disruptor benzyl butyl phthalate (BBP) on the regulation of physical activity in mice. METHODS: Mouse dams were treated with 500 mg·kg·d of BBP or vehicle on gestation days 9-16. Pups were weaned and analyzed for voluntary physical activity levels, puberty development, sex hormone levels, and body composition during the 20-wk period. RESULTS: Seventy-three offspring from BBP-treated dams were studied (n = 43 males and n = 30 females). Endocrine disruption was indicated by decreased anogenital distances in BBP-treated male offspring at 10 (P = 0.001) and 20 wk (P = 0.038) and delayed vaginal openings in BBP-treated female offspring (P = 0.001). Further, there was a significant decrease in serum testosterone concentration in male mice between control and BBP at 10 wk (P = 0.039) and at 20 wk (P = 0.022). In female mice, there was a significant increase in serum testosterone concentration in BBP mice at 20 wk (P = 0.002) and a significant increase in estrogen (estradiol) concentrations at 20 wk in the control female mice (P = 0.015). Overall, BBP mice ran significantly less distance (males, P = 0.008; females, P = 0.042) than controls. Other than a significant increase in BBP-treated males in fat mass at 20 wk (P = 0.040), there was no significant decrease in weight, lean mass, or fat mass in either female or male mice, regardless of treatment. CONCLUSION: Maternal endocrine disruption altered hormone response, but not body composition in either sex of offspring, with a corresponding decreased activity throughout early adulthood in all offspring. These results suggest that exposure to common environmental endocrine disruptors in utero can reduce and alter physical activity levels in offspring.

Heart Rate Response of Professional Musicians When Playing Music.

OBJECTIVES: The primary aim was to determine the level of physiological stress evoked while playing music in a standing position as indicated by heart rate (HR) response. A secondary aim was to analyze the effect of music genre (classic rock, western, contemporary Christian, and metal rock) on the relative HR response. Lastly, we considered potential physiological initiators of the music-playing-induced HR response. METHODS: HR response was monitored in 27 professional musicians (3 women, 24 men) between the ages of 21 and 67 yrs old during rehearsal and public performances. The percent maximal HR (%MHR) evoked was determined by taking a percentage of the age-predicted maximal HR for each musician and comparing the average %MHR in each genre during public and rehearsal events. The role of the potential initiators of these responses (e.g., number of years playing in public, event type, instrument type, tempo, etc.) was determined using multiple regression analyses. RESULTS: The overall average %MHR responses were 52 ± 5% and 59 ± 5% during rehearsal and public performances, respectively, with genre type having a significant effect on the HR response (p=0.01). Body mass index and tempo were each found to be significant contributors to the HR response while playing music (r²=0.506, p=0.001). CONCLUSION: Playing music professionally evokes considerable increases in HR response, with music genre influencing the level of the physiological response. We concluded that 50% of the HR response while playing music was associated with body mass index, music tempo, and instrument type.

Differential protein expression in the nucleus accumbens of high and low active mice.

Physical inactivity is associated with the development of a variety of chronic illnesses. Literature has shown that physical activity is genetically regulated; however there is limited information on the mechanisms that influence this process with existing studies primarily focused on genomic and/or transcription association studies. There have been no studies to determine differential protein expression in the nucleus accumbens, the brain site thought to be involved in activity regulation, between high and low active animals. We compared the global nucleus accumbens proteome signature from known high- and low-active mice and identified seven differentially expressed proteins. Low active mice generally over expressed proteins associated with neural stress (Stress 70 protein and V type proton ATPase catalytic subunit A), and the high-active mice over expressed proteins associated with metabolism (creatine kinase B, succinyl-CoA ligase). Previously suggested mechanisms associated with activity regulation in the nucleus accumbens have centered on dopamine receptor 1 and endocannabinoid receptor 1. However, these proteins and the associated pathways were not differentially expressed between high and low active mice. In conclusion, protein expression must be determined as part of the effort to identify involved mechanisms in regulating activity and there appears to be separate nucleus accumbens proteome signatures associated with high- and low-active mice.

Differential skeletal muscle proteome of high- and low-active mice.

Physical inactivity contributes to cardiovascular disease, type II diabetes, obesity, and some types of cancer. While the literature is clear that there is genetic regulation of physical activity with existing gene knockout data suggesting that skeletal muscle mechanisms contribute to the regulation of activity, actual differences in end-protein expression between high- and low-active mice have not been investigated. This study used two-dimensional differential gel electrophoresis coupled with mass spectrometry to evaluate the proteomic differences between high-active (C57L/J) and low-active (C3H/HeJ) mice in the soleus and extensor digitorum longus (EDL). Furthermore, vivo-morpholinos were used to transiently knockdown candidate proteins to confirm their involvement in physical activity regulation. Proteins with higher expression patterns generally fell into the calcium-regulating and Krebs (TCA) cycle pathways in the high-active mice (e.g., annexin A6, P = 0.0031; calsequestrin 1; P = 0.000025), while the overexpressed proteins in the low-active mice generally fell into cytoskeletal structure- and electron transport chain-related pathways (e.g., ATPase, P = 0.031; NADH dehydrogenase, P = 0.027). Transient knockdown of annexin A6 and calsequestrin 1 protein of high-active mice with vivo-morpholinos resulted in decreased physical activity levels (P = 0.001). These data suggest that high- and low-active mice have unique protein expression patterns and that each pattern contributes to the peripheral capability to be either high- or low-active, suggesting that different specific mechanisms regulate activity leading to the high- or low-activity status of the animal.