P7C3 ameliorates barium chloride-induced skeletal muscle injury activating transcriptomic and epigenetic modulation of myogenic regulatory factors.

Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1-anilino-3-(3,6-dibromocarbazol-9-yl) propan-2-ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl2) into the tibialis anterior (TA) muscle in C57Bl/6J wild-type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl2-induced TA muscle injury was robust and the P7C3-treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle-treated mice. The specificity of P7C3 was evaluated using Nampt+/- mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA-sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh-treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh-treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation-reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation-quantitative polymerase chain reaction (qPCR) and reverse transcription-qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3-treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3-treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl2-injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide-induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis.

Denervation Atrophy of Skeletal Muscle is Not Influenced by Numb Levels in Mice.

Skeletal muscle undergoes rapid and extensive atrophy following nerve transection though the underlying mechanisms remain incompletely understood. We previously showed transiently elevated Notch 1 signaling in denervated skeletal muscle that was abrogated by administration of nandrolone (an anabolic steroid) combined with replacement doses of testosterone. Numb is an adaptor molecule present in myogenic precursors and skeletal muscle fibers that is vital for normal tissue repair after muscle injury and for skeletal muscle contractile function. It is unclear whether the increase in Notch signaling observed in denervated muscle contributes to denervation and whether expression of Numb in myofibers slows denervation atrophy. To address these questions, the degree of denervation atrophy, Notch signaling, and Numb expression was studied over time after denervation in C57B6J mice treated with nandrolone, nandrolone plus testosterone or vehicle. Nandrolone increased Numb expression and reduced Notch signaling. Neither nandrolone alone nor nandrolone plus testosterone changed the rate of denervation atrophy. We next compared rates of denervation atrophy between mice with conditional, tamoxifen-inducible knockout of Numb in myofibers and genetically identical mice treated with vehicle. Numb cKO had no effect on denervation atrophy in this model. Taken together, the data indicate that loss of Numb in myofibers does not alter the course of denervation atrophy and that upregulation of Numb and blunting of the denervation-atrophy induced activation of Notch do not change the course of denervation atrophy.

NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.

The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.

Ionic Silicon Protects Oxidative Damage and Promotes Skeletal Muscle Cell Regeneration.

Volumetric muscle loss injuries overwhelm the endogenous regenerative capacity of skeletal muscle, and the associated oxidative damage can delay regeneration and prolong recovery. This study aimed to investigate the effect of silicon-ions on C2C12 skeletal muscle cells under normal and excessive oxidative stress conditions to gain insights into its role on myogenesis during the early stages of muscle regeneration. In vitro studies indicated that 0.1 mM Si-ions into cell culture media significantly increased cell viability, proliferation, migration, and myotube formation compared to control. Additionally, MyoG, MyoD, Neurturin, and GABA expression were significantly increased with addition of 0.1, 0.5, and 1.0 mM of Si-ion for 1 and 5 days of C2C12 myoblast differentiation. Furthermore, 0.1-2.0 mM Si-ions attenuated the toxic effects of H2O2 within 24 h resulting in increased cell viability and differentiation. Addition of 1.0 mM of Si-ions significantly aid cell recovery and protected from the toxic effect of 0.4 mM H2O2 on cell migration. These results suggest that ionic silicon may have a potential effect in unfavorable situations where reactive oxygen species is predominant affecting cell viability, proliferation, migration, and differentiation. Furthermore, this study provides a guide for designing Si-containing biomaterials with desirable Si-ion release for skeletal muscle regeneration.

The skeletal muscles of mice infected with Plasmodium berghei and Plasmodium chabaudi reveal a crosstalk between lipid mediators and gene expression.

BACKGROUND: Malaria is one of the most prevalent infectious disease in the world with 3.2 billion humans at risk. Malaria causes splenomegaly and damage in other organs including skeletal muscles. Skeletal muscles comprise nearly 50% of the human body and are largely responsible for the regulation and modulation of overall metabolism. It is essential to understand how malaria damages muscles in order to develop effective preventive measures and/or treatments. Using a pre-clinical animal model, the potential molecular mechanisms of Plasmodium infection affecting skeletal muscles of mice were investigated. METHODS: Mouse Signal Transduction Pathway Finder PCR Array was used to monitor gene expression changes of 10 essential signalling pathways in skeletal muscles from mice infected with Plasmodium berghei and Plasmodium chabaudi. Then, a new targeted-lipidomic approach using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to profile 158 lipid signalling mediators (LMs), mostly eicosanoids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was applied. Finally, 16 key LMs directly associated with inflammation, oxidative stress, and tissue healing in skeletal muscles, were quantified. RESULTS: The results showed that the expression of key genes altered by Plasmodium infection is associated with inflammation, oxidative stress, and atrophy. In support to gene profiling results, lipidomics revealed higher concentrations of LMs in skeletal muscles directly related to inflammatory responses, while on the levels of LMs crucial in resolving inflammation and tissue repair reduced significantly. CONCLUSION: The results provide new insights into the molecular mechanisms of malaria-induced muscle damage and revealed a potential mechanism modulating inflammation in malarial muscles. These pre-clinical studies should help with future clinical studies in humans aimed at monitoring of disease progression and development of specific interventions for the prevention and mitigation of long-term chronic effects on skeletal muscle function.

Novel 3D-printed methacrylated chitosan-laponite nanosilicate composite scaffolds enhance cell growth and biomineral formation in MC3T3 pre-osteoblasts.

This study compared the effect of gelatin- and chitosan-based scaffolds on osteoblast biomineralization. These scaffolds have been modified using methacrylate and laponite nanosilicates to improve their mechanical strength and support osteoblast function. Scaffold materials were prepared to have the same compressive strength (14-15 MPa) such that differences in cell response would be isolated to differences in biopolymer chemistry. The materials were tested for rheological properties to optimize the bio-ink for successful 3D printing using a robocast-assisted deposition system. Osteoblasts were cultured on the surface of 3D-printed methacrylated chitosan-laponite (MAC-Lp), methacrylated gelatin-laponite (MAG-Lp), MAC, and MAG scaffolds. MAC-Lp scaffolds showed increased cell viability, cell growth, and biomineral formation as compared to MAG-Lp scaffolds. FTIR results showed the presence of higher biomineral phosphate and extracellular matrix (ECM) collagen-like amide formation on MAC-Lp scaffolds as compared to MAG-Lp scaffolds. MAC-Lp scaffolds showed increased density of ECM-like tissue from SEM analysis, stained mineral nodules from Alizarin staining, and the existence of Ca─P species evident by X-ray absorbance near edge structure analysis. In conclusion, MAC-Lp scaffolds enhanced osteoblast growth and biomineral formation as compared to MAG-Lp scaffolds.

Transitioning from acute to chronic pain: a simulation study of trajectories of low back pain.

BACKGROUND: Identifying how pain transitions from acute to chronic is critical in designing effective prevention and management techniques for patients' well-being, physically, psychosocially, and financially. There is an increasingly pressing need for a quantitative and predictive method to evaluate how low back pain trajectories are classified and, subsequently, how we can more effectively intervene during these progression stages. METHODS: In order to better understand pain mechanisms, we investigated, using computational modeling, how best to describe pain trajectories by developing a platform by which we studied the transition of acute chronic pain. RESULTS: The present study uses a computational neuroscience-based method to conduct such trajectory research, motivated by the use of hypothalamic-pituitary-adrenal (HPA) axis activity-history over a time-period as a way to mimic pain trajectories. A numerical simulation study is presented as a "proof of concept" for this modeling approach. CONCLUSIONS: This model and its simulation results have highlighted the feasibility and the potential of developing such a broader model for patient evaluations.

Multi-Staged Regulation of Lipid Signaling Mediators during Myogenesis by COX-1/2 Pathways.

Cyclooxygenases (COXs), including COX-1 and -2, are enzymes essential for lipid mediator (LMs) syntheses from arachidonic acid (AA), such as prostaglandins (PGs). Furthermore, COXs could interplay with other enzymes such as lipoxygenases (LOXs) and cytochrome P450s (CYPs) to regulate the signaling of LMs. In this study, to comprehensively analyze the function of COX-1 and -2 in regulating the signaling of bioactive LMs in skeletal muscle, mouse primary myoblasts and C2C12 cells were transfected with specific COX-1 and -2 siRNAs, followed by targeted lipidomic analysis and customized quantitative PCR gene array analysis. Knocking down COXs, particularly COX-1, significantly reduced the release of PGs from muscle cells, especially PGE2 and PGF2α, as well as oleoylethanolamide (OEA) and arachidonoylethanolamine (AEA). Moreover, COXs could interplay with LOXs to regulate the signaling of hydroxyeicosatetraenoic acids (HETEs). The changes in LMs are associated with the expression of genes, such as Itrp1 (calcium signaling) and Myh7 (myogenic differentiation), in skeletal muscle. In conclusion, both COX-1 and -2 contribute to LMs production during myogenesis in vitro, and COXs could interact with LOXs during this process. These interactions and the fine-tuning of the levels of these LMs are most likely important for skeletal muscle myogenesis, and potentially, muscle repair and regeneration.

Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility.

Skeletal muscle dysfunction accompanies the clinical disorders of chronic kidney disease (CKD) and hereditary hypophosphatemic rickets. In both disorders, fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D metabolism, becomes chronically elevated. FGF23 has been shown to play a direct role in cardiac muscle dysfunction; however, it is unknown whether FGF23 signaling can also directly induce skeletal muscle dysfunction. We found expression of potential FGF23 receptors ( Fgfr1-4) and α-Klotho in muscles of two animal models (CD-1 and Cy/+ rat, a naturally occurring rat model of chronic kidney disease-mineral bone disorder) as well as C2C12 myoblasts and myotubes. C2C12 proliferation, myogenic gene expression, oxidative stress marker 8-OHdG, intracellular Ca2+ ([Ca2+]i), and ex vivo contractility of extensor digitorum longus (EDL) or soleus muscles were assessed after treatment with various amounts of FGF23. FGF23 (2-100 ng/ml) did not alter C2C12 proliferation, expression of myogenic genes, or oxidative stress after 24- to 72-h treatment. Acute or prolonged FGF23 treatment up to 6 days did not alter C2C12 [Ca2+]i handling, nor did acute treatment with FGF23 (9-100 ng/ml) affect EDL and soleus muscle contractility. In conclusion, although skeletal muscles express the receptors involved in FGF23-mediated signaling, in vitro FGF23 treatments failed to directly alter skeletal muscle development or function under the conditions tested. We hypothesize that other endogenous substances may be required to act in concert with FGF23 or apart from FGF23 to promote muscle dysfunction in hereditary hypophosphatemic rickets and CKD.

Nanodrug delivery platform for glucocorticoid use in skeletal muscle injury.

Glucocorticoids are utilized for their anti-inflammatory properties in the skeletal muscle and arthritis. However, the major drawback of use of glucocorticoids is that it leads to senescence and toxicity. Therefore, based on the idea that decreasing particle size allows for increased surface area and bioavailability of the drug, in the present study, we hypothesized that nanodelivery of dexamethasone will offer increased efficacy and decreased toxicity. The dexamethasone-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared using nanoprecipitation method. The morphological characteristics of the nanoparticles were studied under scanning electron microscope. The particle size of nanoparticles was 217.5 ± 19.99 nm with polydispersity index of 0.14 ± 0.07. The nanoparticles encapsulation efficiency was 34.57% ± 1.99% with in vitro drug release profile exhibiting a sustained release pattern over 10 days. We identified improved skeletal muscle myoblast performance with improved closure of the wound along with increased cell viability at 10 nmol/L nano-dexamethasone-PLGA. However, dexamethasone solution (1 µmol/L) was injurious to cells because the migration efficiency was decreased. In addition, the use of dexamethasone nanoparticles decreased lipopolysaccharide-induced lactate dehydrogenase release compared with dexamethasone solution. Taken together, the present study clearly demonstrates that delivery of PLGA-dexamethasone nanoparticles to the skeletal muscle cells is beneficial for treating inflammation and skeletal muscle function.

Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age.

Conditional deletion of Mbtps1 (cKO) protease in bone osteocytes leads to an age-related increase in mass (12%) and in contractile force (30%) in adult slow twitch soleus muscles (SOL) with no effect on fast twitch extensor digitorum longus muscles. Surprisingly, bone from 10-12-month-old cKO animals was indistinguishable from controls in size, density, and morphology except for a 25% increase in stiffness. cKO SOL exhibited increased expression of Pax7, Myog, Myod1, Notch, and Myh3 and 6-fold more centralized nuclei, characteristics of postnatal regenerating muscle, but only in type I myosin heavy chain-expressing cells. Increased expression of gene pathways mediating EGF receptor signaling, circadian exercise, striated muscle contraction, and lipid and carbohydrate oxidative metabolism were also observed in cKO SOL. This muscle phenotype was not observed in 3-month-old mice. Although Mbtps1 mRNA and protein expression was reduced in cKO bone osteocytes, no differences in Mbtps1 or cre recombinase expression were observed in cKO SOL, explaining this age-related phenotype. Understanding bone-muscle cross-talk may provide a fresh and novel approach to prevention and treatment of age-related muscle loss.

The effect of malaria and anti-malarial drugs on skeletal and cardiac muscles.

Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.

Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation.

The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.

Type 1 inositol (1,4,5)-trisphosphate receptor activates ryanodine receptor 1 to mediate calcium spark signaling in adult mammalian skeletal muscle.

Functional coupling between inositol (1,4,5)-trisphosphate receptor (IP(3)R) and ryanodine receptor (RyR) represents a critical component of intracellular Ca(2+) signaling in many excitable cells; however, the role of this mechanism in skeletal muscle remains elusive. In skeletal muscle, RyR-mediated Ca(2+) sparks are suppressed in resting conditions, whereas application of transient osmotic stress can trigger activation of Ca(2+) sparks that are restricted to the periphery of the fiber. Here we show that onset of these spatially confined Ca(2+) sparks involves interaction between activation of IP(3)R and RyR near the sarcolemmal membrane. Pharmacological prevention of IP(3) production or inhibition of IP(3)R channel activity abolishes stress-induced Ca(2+) sparks in skeletal muscle. Although genetic ablation of the type 2 IP(3)R does not appear to affect Ca(2+) sparks in skeletal muscle, specific silencing of the type 1 IP(3)R leads to ablation of stress-induced Ca(2+) sparks. Our data indicate that membrane-delimited signaling involving cross-talk between IP(3)R1 and RyR1 contributes to Ca(2+) spark activation in skeletal muscle.

Visual gene-network analysis reveals the cancer gene co-expression in human endometrial cancer.

BACKGROUND: Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer-associated molecules and signaling networks would be useful for the detection and monitoring of malignancy, improving clinical cancer therapy, and personalization of treatments. RESULTS: ECs-specific gene co-expression networks were constructed by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Important pathways and putative cancer hub genes contribution to tumorigenesis of ECs were identified. An elastic-net regularized classification model was built using the cancer hub gene signatures to predict the phenotypic characteristics of ECs. The 19 cancer hub gene signatures had high predictive power to distinguish among three key principal features of ECs: grade, type, and stage. Intriguingly, these hub gene networks seem to contribute to ECs progression and malignancy via cell-cycle regulation, antigen processing and the citric acid (TCA) cycle. CONCLUSIONS: The results of this study provide a powerful biomarker discovery platform to better understand the progression of ECs and to uncover potential therapeutic targets in the treatment of ECs. This information might lead to improved monitoring of ECs and resulting improvement of treatment of ECs, the 4th most common of cancer in women.

Endocrine crosstalk between muscle and bone.

The musculoskeletal system is a complex organ comprised of the skeletal bones, skeletal muscles, tendons, ligaments, cartilage, joints, and other connective tissue that physically and mechanically interact to provide animals and humans with the essential ability of locomotion. This mechanical interaction is undoubtedly essential for much of the diverse shape and forms observed in vertebrates and even in invertebrates with rudimentary musculoskeletal systems such as fish. It makes sense from a historical point of view that the mechanical theories of musculoskeletal development have had tremendous influence of our understanding of biology, because these relationships are clear and palpable. Less visible to the naked eye or even to the microscope is the biochemical interaction among the individual players of the musculoskeletal system. It was only in recent years that we have begun to appreciate that beyond this mechanical coupling of muscle and bones, these 2 tissues function at a higher level through crosstalk signaling mechanisms that are important for the function of the concomitant tissue. Our brief review attempts to present some of the key concepts of these new concepts and is outline to present muscles and bones as secretory/endocrine organs, the evidence for mutual genetic and tissue interactions, pathophysiological examples of crosstalk, and the exciting new directions for this promising field of research aimed at understanding the biochemical/molecular coupling of these 2 intimately associated tissues.

Skeletal muscle troponin as a novel biomarker to enhance assessment of the impact of strength training on fall prevention in the older adults.

BACKGROUND: Loss of muscle mass and strength (i.e., sarcopenia) in the older adults is a strong predictor of falls, with subsequent morbidity and inability to execute activities of daily living. Use of biomarkers may enhance assessment of effects of community-based exercise interventions aimed at improving muscle strength. OBJECTIVE: The aim of this study was to investigate the use of troponin as a newly proposed biomarker of skeletal muscle health when determining the outcomes of strength-training programs designed for community-dwelling adults over the age of 65 years. METHODS: Outcomes of two strength training programs ("Peer Exercise Program Promotes Independence" and "Stay Strong, Stay Healthy") were assessed using physical performance tests designed for senior fitness evaluation, grip strength, and changes in serum levels of skeletal muscle-specific troponin T (sTnT). RESULTS: Improvement in physical performance, including a significant increase in grip strength, was associated with a significant reduction in serum levels of sTnT. DISCUSSION: Findings from these studies suggest that, when "Peer Exercise Program Promotes Independence" and "Stay Strong, Stay Healthy" are implemented for at least 10 weeks, significant gains in strength are achieved. This strength improvement was associated with a reduction in serum levels of troponin, supporting the use of troponin as a novel biomarker of muscle health in the assessment of strength training programs for the older adults. Reduced sTnT after exercise intervention suggests that skeletal muscles become stronger and less susceptible to damage because of the exercise regimens.

A randomized-controlled trial pilot study examining the neurodevelopmental effects of a 5-week M Technique intervention on very preterm infants.

PURPOSE: To systematically test the cumulative effect of the M Technique on infant neurodevelopment in hospitalized very preterm infants. DESIGN: A pilot randomized controlled trial (RCT). SUBJECTS: Twenty very preterm infants (<30 weeks gestation with average birth weights <1000 g) were randomly assigned to nontreatment or treatment groups. The study period began once the infants reached 30 weeks postmenstrual age (PMA). METHODS: Each infant received standard neonatal intensive unit (NICU) care or standard NICU care plus a 7-minute M Technique session, 6 times per week for 5 weeks. Neurobehavioral development (using the NICU Network Neurobehavioral Scale [NNNS]) and growth velocity (difference in infant weight at the beginning and end of protocol) were compared between the 2 groups. Physiologic parameters (heart rate, respiratory rate, and oxygen saturations) and infant behavioral states were measured 5 minutes before, during, and up to 10 minutes postintervention continuously on all infants in the treatment group at 3 different gestational time points (30, 32, and 34 weeks PMA) over the 5-week period. RESULTS: Mann-Whitney U analyses revealed no differences between the 2 groups on all 12 NNNS summary score domains but a difference in growth velocity between the 2 groups (P = 0.005). Repeated-measures analysis of variance revealed significant physiologic differences of mean heart rate, respiratory rate, and SaO2 (F = 41.116, P < 0.0005) and behavioral states (F = 38.564, P < 0.0005) from baseline to 10 minutes after the M Technique intervention across all 3 time points. State scores decreased from baseline (M = 6.11) to post intervention (M = 1.4) at all 3 time points. CONCLUSIONS: This pilot RCT demonstrates the utility of the M Technique in hospitalized very preterm infants starting at 30 weeks PMA with notable evidence of positive weight, physiological, and behavioral state adaptations. Additional research is needed with a larger, randomized design to determine short- and long-term effects specifically related to neurological outcomes.

Physiology of Mechanotransduction: How Do Muscle and Bone "Talk" to One Another?

The complexity of cell interactions with their microenvironment and their ability to communicate at the autocrine, paracrine, and endocrine levels has gradually but significantly evolved in the last three decades. The musculoskeletal system has been historically recognized to be governed by a relationship of proximity and function, chiefly dictated by mechanical forces and the work of gravity itself. In this review article, we first provide a historical overview of the biomechanical theory of bone- muscle interactions. Next, we expand to detail the significant evolution in our understanding of the function of bones and muscles as secretory organs. Then, we review and discuss new evidence in support of a biochemical interaction between these two tissues. We then propose that these two models of interaction are complementary and intertwined providing for a new frontier for the investigation of how bone-muscle cross talk could be fully explored for the targeting of new therapies for musculoskeletal diseases, particularly the twin conditions of aging, osteoporosis and sarcopenia. In the last section, we explore the bone-muscle cross talk in the context of their interactions with other tissues and the global impact of these multi-tissue interactions on chronic diseases.

Both enantiomers of ß-aminoisobutyric acid BAIBA regulate Fgf23 via MRGPRD receptor by activating distinct signaling pathways in osteocytes.

With exercise, muscle and bone produce factors with beneficial effects on brain, fat, and other organs. Exercise in mice increased fibroblast growth factor 23 (FGF23), urine phosphate, and the muscle metabolite L-ß-aminoisobutyric acid (L-BAIBA), suggesting that L-BAIBA may play a role in phosphate metabolism. Here, we show that L-BAIBA increases in serum with exercise and elevates Fgf23 in osteocytes. The D enantiomer, described to be elevated with exercise in humans, can also induce Fgf23 but through a delayed, indirect process via sclerostin. The two enantiomers both signal through the same receptor, Mas-related G-protein-coupled receptor type D, but activate distinct signaling pathways; L-BAIBA increases Fgf23 through Gαs/cAMP/PKA/CBP/ß-catenin and Gαq/PKC/CREB, whereas D-BAIBA increases Fgf23 indirectly through sclerostin via Gαi/NF-κB. In vivo, both enantiomers increased Fgf23 in bone in parallel with elevated urinary phosphate excretion. Thus, exercise-induced increases in BAIBA and FGF23 work together to maintain phosphate homeostasis.