Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC.

Morphologic and histologic characterization of sheep and porcine TMJ as large animal models for tissue engineering applications.

Objective: The aim of this study was to compare and characterize the structural and ultrastructural organization of the temporomandibular joint (TMJ) between two large animal models for use in the development of tissue engineering strategies.

Materials And Methods: Whole TMJs from sheep and pigs were evaluated with micro-computed tomography (μCT) for morphology and quantitative analyses of bone parameters. Histological examination was performed on the TMJ disc and its attachments to investigate regional distribution of collagen, elastin, and glycosaminoglycans (GAGs).

Starring or Supporting Role? Satellite Cells and Skeletal Muscle Fiber Size Regulation.

Recent loss-of-function studies show that satellite cell depletion does not promote sarcopenia or unloading-induced atrophy, and does not prevent regrowth. Although overload-induced muscle fiber hypertrophy is normally associated with satellite cell-mediated myonuclear accretion, hypertrophic adaptation proceeds in the absence of satellite cells in fully grown adult mice, but not in young growing mice. Emerging evidence also indicates that satellite cells play an important role in remodeling the extracellular matrix during hypertrophy.

Reanalysis of parabiosis of obesity mutants in the age of leptin.

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect.

Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis.

The ability of skeletal muscle to hypertrophy in response to a growth stimulus is known to be compromised in older individuals. We hypothesized that a change in the expression of protein-encoding genes in response to a hypertrophic stimulus contributes to the blunted hypertrophy observed with aging. To test this hypothesis, we determined gene expression by microarray analysis of plantaris muscle from 5- and 25-mo-old mice subjected to 1, 3, 5, 7, 10, and 14 days of synergist ablation to induce hypertrophy.

Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue.

Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2.

Aged Muscle Demonstrates Fiber-Type Adaptations in Response to Mechanical Overload, in the Absence of Myofiber Hypertrophy, Independent of Satellite Cell Abundance.

Although sarcopenia, age-associated loss of muscle mass and strength, is neither accelerated nor exacerbated by depletion of muscle stem cells, satellite cells, we hypothesized that adaptation in sarcopenic muscle would be compromised. To test this hypothesis, we depleted satellite cells with tamoxifen treatment of Pax7(CreER)-DTA mice at 4 months of age, and 20 months later subjected the plantaris muscle to 2 weeks of mechanical overload. We found myofiber hypertrophy was impaired in aged mice regardless of satellite cell content.

Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia.

A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives.

Automatic Myonuclear Detection in Isolated Single Muscle Fibers Using Robust Ellipse Fitting and Sparse Representation.

Accurate and robust detection of myonuclei in isolated single muscle fibers is required to calculate myonuclear domain size. However, this task is challenging because: 1) shape and size variations of the nuclei, 2) overlapping nuclear clumps, and 3) multiple z-stack images with out-of-focus regions. In this paper, we have proposed a novel automatic detection algorithm to robustly quantify myonuclei in isolated single skeletal muscle fibers.

Engineered skeletal muscle units for repair of volumetric muscle loss in the tibialis anterior muscle of a rat.

Volumetric muscle loss (VML) is the traumatic, degenerative, or surgical loss of muscle tissue, which may result in function loss and physical deformity. To date, clinical treatments for VML--the reflected muscle flap or transferred muscle graft--are limited by tissue availability and donor site morbidity. To address the need for more innovative skeletal muscle repair options, our laboratory has developed scaffoldless tissue-engineered skeletal muscle units (SMUs), multiphasic tissue constructs composed of engineered skeletal muscle with engineered bone-tendon ends, myotendinous junctions, and entheses, which in vitro can produce force both spontaneously and in response to electrical stimulation.

Isolation and Purification of Satellite Cells for Skeletal Muscle Tissue Engineering.

Engineered skeletal muscle holds promise as a source of graft tissue for the repair of traumatic injuries such as volumetric muscle loss. The resident skeletal muscle stem cell, the satellite cell, has been identified as an ideal progenitor for tissue engineering due to its role as an essential player in the potent skeletal muscle regeneration mechanism. A significant challenge facing tissue engineers, however, is the isolation of sufficiently large satellite cell populations with high purity.

Regulation of the muscle fiber microenvironment by activated satellite cells during hypertrophy.

Our aim in the current study was to determine the necessity of satellite cells for long-term muscle growth and maintenance. We utilized a transgenic Pax7-DTA mouse model, allowing for the conditional depletion of > 90% of satellite cells with tamoxifen treatment. Synergist ablation surgery, where removal of synergist muscles places functional overload on the plantaris, was used to stimulate robust hypertrophy.

Engineering muscle constructs for the creation of functional engineered musculoskeletal tissue.

Volumetric muscle loss (VML) is a disabling condition in which current clinical procedures are suboptimal. The field of tissue engineering has many promising strategies for the creation of functional skeletal muscle in vitro. However, there are still two key limitations that prevent it from becoming a solution for treating VML.

Automated fiber-type-specific cross-sectional area assessment and myonuclei counting in skeletal muscle.

Skeletal muscle is an exceptionally adaptive tissue that compromises 40% of mammalian body mass. Skeletal muscle functions in locomotion, but also plays important roles in thermogenesis and metabolic homeostasis. Thus characterizing the structural and functional properties of skeletal muscle is important in many facets of biomedical research, ranging from myopathies to rehabilitation sciences to exercise interventions aimed at improving quality of life in the face of chronic disease and aging.

Muscle-specific substrate use during cycle exercise at 1 G: implications for astronaut muscle health.

Introduction: Studies of real and simulated microgravity exposure show the lower limb muscles atrophy to the greatest extent, with the calf muscles being most affected and most difficult to target with exercise countermeasures. This ground-based study examined the metabolic involvement of the thigh and calf muscles during two cycle exercise protocols (moderate and high intensity) central to the exercise countermeasures program on the International Space Station.

Methods: Intramuscular glycogen and triglyceride levels were quantified in the vastus lateralis and soleus muscles before and after a moderate (current ISS prescription: 45 min at 55% VO(2max), 131 +/- 12 W) and high (proposed ISS prescription: 8 x 30-s intervals at 150% VO(2max), 459 +/- 34 W) intensity cycle exercise bout in nine individuals.

Time course of gene expression during mouse skeletal muscle hypertrophy.

The purpose of this study was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5, 7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the number of differentially expressed genes (cutoffs ≥2-fold increase or ≥50% decrease compared with control muscle) revealed three gene expression patterns during overload-induced hypertrophy: early (1 day), intermediate (3, 5, and 7 days), and late (10 and 14 days) patterns.

Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance.

Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks.

Automated image analysis of skeletal muscle fiber cross-sectional area.

Morphological characteristics of muscle fibers, such as fiber size, are critical factors that determine the health and function of the muscle. However, at this time, quantification of muscle fiber cross-sectional area is still a manual or, at best, a semiautomated process. This process is labor intensive, time consuming, and prone to errors, leading to high interobserver variability.

Association of fibromyalgia with altered skeletal muscle characteristics which may contribute to postexertional fatigue in postmenopausal women.

Objective: To identify muscle physiologic properties that may contribute to postexertional fatigue and malaise in women with fibromyalgia (FM).

Methods: Healthy postmenopausal women with (n = 11) and without (n = 11) FM, ages 51-70 years, participated in this study. Physical characteristics and responses to self-reported questionnaires were evaluated.

Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy.

Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal.

The effect of pre-exercise carbohydrate supplementation on anaerobic exercise performance in adolescent males.

Carbohydrate (CHO) consumption before anaerobic exercise was studied in 13 adolescent boys (15.2 ± 0.9 yrs).

Evaluating the prediction of maximal heart rate in children and adolescents.

In this study, we compared measured maximal heart rate (HRmax) to two different HRmax prediction equations [22 - age and 208 - 0.7(age)] in 52 children ages 7-17 years. We determined the relationship of chronological age, maturational age, and resting HR to measured HRmax and assessed seated resting HR and HRmax during a graded exercise test.

Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults.

Evidence suggests that consumption of over-the-counter cyclooxygenase (COX) inhibitors may interfere with the positive effects that resistance exercise training has on reversing sarcopenia in older adults. This study examined the influence of acetaminophen or ibuprofen consumption on muscle mass and strength during 12 wk of knee extensor progressive resistance exercise training in older adults. Thirty-six individuals were randomly assigned to one of three groups and consumed the COX-inhibiting drugs in double-blind placebo-controlled fashion: placebo (67 ± 2 yr; n = 12), acetaminophen (64 ± 1 yr; n = 11; 4 g/day), and ibuprofen (64 ± 1 yr; n = 13; 1.

Impact of sex and chronic resistance training on human patellar tendon dry mass, collagen content, and collagen cross-linking.

Collagen content and cross-linking are believed to be major determinants of tendon structural integrity and function. Sex and chronic resistance training have been shown to alter tendon function and may also alter the key structural features of tendon. Patellar tendon biopsies were taken from untrained men [n = 8, 1 repetition maximum (RM) = 53 +/- 3 kg], untrained women (n = 8, 1 RM = 29 +/- 2 kg), and resistance-trained (10 +/- 1 yr of training) men (n = 8, 1 RM = 71 +/- 6 kg).