Muscle Physiology Research Articles

EXERCISE SCIENCE IN HIGH SCHOOL BIOLOGY TEXTBOOKS

ABSTRACT The content of high school textbooks related to physical activity and exercise is of utmost importance because physical activity and exercise are considered important tools in maintaining and improving health. Our objective was to analyze the presence and quality of exercise science content in high school biology textbooks approved by the National Textbook Plan. A guiding document was developed to enable the analysis of the textbooks. The topics investigated were: I) the extent of content related to exercise science; II) misconceptions about exercise science; III) health benefits attributed to exercise. The academic qualifications of the textbook authors were also analyzed. All analyzed textbooks (n = 9) featured some degree of exercise science content. In addition, ~67% of textbooks analyzed had at least one misconception regarding exercise science, the most common being related to biochemistry and muscle physiology. Also, 93.8% of the authors had undergraduate degrees in biological sciences; 43.8% had doctoral degrees. In conclusion, all high school biology textbooks presented content related to exercise science; however, most of them presented at least one misconception regarding exercise science. Thus, we suggest that the Brazilian National Textbook Plan should improve the criteria for analyzing biology textbooks. Level of Evidence III; Economic and decision analyses - Development of an economic or decision model.

Gaining insight into the role of FoxO1 in the progression of disuse-induced skeletal muscle atrophy.

Expression of FoxO transcription factors increases during certain forms of atrophy. In a dephosphorylated state, FoxOs participate in ubiquitin-mediated proteasomal degradation through the transcriptional activation of E3-ubiquitin ligases such as MAFbx/atrogin-1 and MuRF1. There is exhaustive research demonstrating that FoxO3a is sufficient to induce MAFbx/atrogin-1 and MuRF-1 expressions. In contrast, the data are conflicting on the requirement of FoxO1 signaling in the activation of the E3-ubiquitin ligases. Moreover, no reports currently exist on the particular role of FoxO1 in the molecular mechanisms involved in the progression of physiological muscle wasting. Here, we have applied the most extensively used rodent model of microgravity/functional unloading to stimulate disuse-induced skeletal muscle atrophy such as rat hindlimb suspension (HS). We showed that inhibition of FoxO1 activity by a selective inhibitor AS1842856 completely reversed an increase in expression of MuRF-1, but not MAFbx/atrogin-1, observed upon HS. Furthermore, we demonstrated that FoxO1 induced upregulation of another E3-ubiquitin-ligase of a MuRF protein family MuRF-2 in skeletal muscle subjected to disuse. Prevention of the MuRF increase upon HS impeded upregulation of transcript expression of a negative regulator of NFATc1 pathway calsarcin-2, which was associated with a partial reversion of MyHC-IId/x and MyHC-IIb mRNA expressions. Importantly, FoxO1 inhibition induced a marked increase in p70S6k phosphorylation, an important stage in the initiation of protein translation, concomitant with the restoration of global protein synthesis in the skeletal muscle of the HS rats. Examination of eIF3f expression and the eEF2k/eEF2 pathway, other factors controlling translation initiation and elongation respectively, did not reveal any impact of FoxO1 on their activity. Lastly, we observed a decrease in transcript levels of Sesn3, but not Sesn1 and Sesn2, upon disuse, which was completely reversed by FoxO1 inhibition. These data demonstrate that FoxO1 signaling contributes to the development of disuse-induced skeletal muscle atrophy, including slow to fast MyHC isoform shift, mostly through upregulation of MuRF-1 and MuRF-2 expression. Furthermore, FoxO1 inhibition is required to recover Sesn3 mRNA expression in atrophic conditions, which likely contributes to the enhanced p70S6k activity and restoration of the protein synthesis rate.

Microvascular response to exercise varies along the length of the tibialis anterior muscle.

Microvascular function is an important component in the physiology of muscle. One of the major parameters, blood perfusion, can be measured noninvasively and quantitatively by arterial spin labeling (ASL) MRI. Most studies using ASL in muscle have only reported data from a single slice, thereby assuming that muscle perfusion is homogeneous within muscle, whereas recent literature has reported proximodistal differences in oxidative capacity and perfusion. Here, we acquired pulsed ASL data in 12 healthy volunteers after dorsiflexion exercise in two slices separated distally by 7cm. We combined this with a Look-Locker scheme to acquire images at multiple postlabeling delays (PLDs) and with a multiecho readout to measure T2 *. This enabled the simultaneous evaluation of quantitative muscle blood flow (MBF), arterial transit time (ATT), and T2 * relaxation time in the tibialis anterior muscle during recovery. Using repeated measures analyses of variance we tested the effect of time, slice location, and their interaction on MBF, ATT, and T2 *. Our results showed a significant difference as a function of time postexercise for all three parameters (MBF: F = 34.0, p< .0001; T2 *: F = 73.7, p< .0001; ATT: F = 13.6, p< .001) and no average differences between slices over the total time postexercise were observed. The interaction effect between time postexercise and slice location was significant for MBF and T2 * (F = 5.5, p= 0.02, F = 6.1, p= 0.02, respectively), but not for ATT (F = 2.2, p= .16). The proximal slice showed a higher MBF and a lower ATT than the distal slice during the first 2 min of recovery, and T2 * showed a delayed response in the distal slice. These results imply a higher perfusion and faster microvascular response to exercise in the proximal slice, in line with previous literature. Moreover, the differences in ATT indicate that it is difficult to correctly determine perfusion based on a single PLD as is commonly performed in the muscle literature.

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity.

The cannabinoid system is ubiquitously present and is classically considered to engage in neural and immunity processes. Yet, the role of the cannabinoid system in the whole body and tissue metabolism via central and peripheral mechanisms is increasingly recognized. The present review provides insights in (i) how cannabinoid signaling is regulated via receptor-independent and -dependent mechanisms and (ii) how these signaling cascades (might) affect skeletal muscle plasticity and physiology. Receptor-independent mechanisms include endocannabinoid metabolism to eicosanoids and the regulation of ion channels. Alternatively, endocannabinoids can act as ligands for different classic (cannabinoid receptor 1 [CB1 ], CB2 ) and/or alternative (e.g.,TRPV1, GPR55) cannabinoid receptors with a unique affinity, specificity, and intracellular signaling cascade (often tissue-specific). Antagonism of CB1 might hold clues to improve oxidative (mitochondrial) metabolism, insulin sensitivity, satellite cell growth, and muscle anabolism, whereas CB2 agonism might be a promising way to stimulate muscle metabolism and muscle cell growth. Besides, CB2 ameliorates muscle regeneration via macrophage polarization towardan anti-inflammatory phenotype, induction of MyoD and myogenin expression and antifibrotic mechanisms. Also TRPV1 and GPR55 contribute to the regulation of muscle growth and metabolism. Future studies should reveal how the cannabinoid system can be targeted to improve muscle quantity and/or quality in conditions such as ageing, disease, disuse, and metabolic dysregulation, taking into account challenges that are inherent to modulation of the cannabinoid system, such as central and peripheral side effects.

Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective.

Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myofiber pathways. These pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. This review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.

Hypothalamus-Muscle Parallel Induction of Metabolic Pathways Following Physical Exercise.

The modern lifestyle requires less physical activity and skills during our daily routine, leading to multiple pathologies related to physical disabilities and energy accessibility. Thus, exploring the mechanisms underlying the metabolic regulation of exercise is crucial. Here, we characterized the effect of forced and voluntary endurance exercises on three key metabolic signaling pathways, sirtuins, AMPK, and mTOR, across several metabolic tissues in mice: brain, muscles, and liver. Both voluntary and forced exercises induced AMPK with higher intensity in the first. The comparison between those metabolic tissues revealed that the hypothalamus and the hippocampus, two brain parts, showed different metabolic signaling activities. Strikingly, despite the major differences in the physiology of muscles and hypothalamic tissues, the hypothalamus replicates the metabolic response of the muscle in response to physical exercise. Specifically, muscles and hypothalamic tissues showed an increase and a decrease in AMPK and mTOR signaling, respectively. Overall, this study reveals new insight into the relation between the hypothalamus and muscles, which enhances the coordination within the muscle–brain axis and potentially improves the systemic response to physical activity performance and delaying health inactivity disorders.

Near-Infrared Spectroscopy Used to Assess Physiological Muscle Adaptations in Exercise Clinical Trials: A Systematic Review.

Simple SummaryIn recent years, physical exercise has been used as a therapeutic strategy in various clinical conditions, with pleiotropic benefits. Near-infrared spectroscopy (NIRS) has been positioned as a tool to analyze effects on muscle oxygenation, also allowing knowledge of adaptations on microvascular levels and muscle metabolism in subjects with central and peripheral vascular alterations, as well as cardiovascular, metabolic, and/or musculoskeletal diseases. This knowledge can help to guide therapeutic exercise specialists in decision making regarding the prescription and follow up of physical exercise as a therapeutic tool in the observation of acute or chronic adaptations to improve efficiency in the treatment and recovery of these patients. This review presents an overview of the effects of exercise clinical trials on muscle oxygenation in different pathologies and the technical characteristics related to the equipment used.Using muscle oxygenation to evaluate the therapeutic effects of physical exercise in pathologies through near-infrared spectroscopy (NIRS) is of great interest. The aim of this review was to highlight the use of muscle oxygenation in exercise interventions in clinical trials and to present the technological characteristics related to the equipment used in these studies. PubMed, WOS, and Scopus databases were reviewed up to December 2021. Scientific articles that evaluated muscle oxygenation after exercise interventions in the sick adult population were selected. The PEDro scale was used to analyze the risk of bias (internal validity). The results were presented grouped in tables considering the risk of bias scores, characteristics of the devices, and the effects of exercise on muscle oxygenation. All the stages were carried out using preferred reporting items for systematic reviews and meta-analyses (PRISMA). The search strategy yielded 820 clinical studies, of which 18 met the eligibility criteria. This review detailed the characteristics of 11 NIRS devices used in clinical trials that used physical exercise as an intervention. The use of this technology made it possible to observe changes in muscle oxygenation/deoxygenation parameters such as tissue saturation, oxyhemoglobin, total hemoglobin, and deoxyhemoglobin in clinical trials of patients with chronic disease. It was concluded that NIRS is a non-invasive method that can be used in clinical studies to detect the effects of physical exercise training on muscle oxygenation, hemodynamics, and metabolism. It will be necessary to unify criteria such as the measurement site, frequency, wavelength, and variables for analysis. This will make it possible to compare different models of exercise/training in terms of time, intensity, frequency, and type to obtain more precise conclusions about their benefits for patients.

H19 inhibition increases HDAC6 and regulates IRS1 levels and insulin signaling in the skeletal muscle during diabetes

BackgroundHistone deacetylases (HDACs) that catalyze removal of acetyl groups from histone proteins, are strongly associated with several diseases including diabetes, yet the precise regulatory events that control the levels and activity of the HDACs are not yet well elucidated.MethodsLevels of H19 and HDACs were evaluated in skeletal muscles of normal and diabetic db/db mice by Western Blot analysis. C2C12 cells were differentiated and transfected with either the scramble or H19 siRNA and the levels of HDACs and Prkab2, Pfkfb3, Srebf1, Socs2, Irs1 and Ppp2r5b were assessed by Western Blot analysis and qRT-PCR, respectively. Levels of H9, HDAC6 and IRS1 were evaluated in skeletal muscles of scramble/ H19 siRNA injected mice and chow/HFD-fed mice.ResultsOur data show that the lncRNA H19 and HDAC6 exhibit inverse patterns of expression in the skeletal muscle of diabetic db/db mice and in C2C12 cells, H19 inhibition led to significant increase in HDAC activity and in the levels of HDAC6, both at the transcript and protein levels. This was associated with downregulation of IRS1 levels that were prevented in the presence of the HDAC inhibitor, SAHA, and HDAC6 siRNA suggesting the lncRNA H19-HDAC6 axis possibly regulates cellular IRS1 levels. Such patterns of H19, HDAC6 and IRS1 expression were also validated and confirmed in high fat diet-fed mice where as compared to normal chow-fed mice, H19 levels were significantly inhibited in the skeletal muscle of these mice and this was accompanied with elevated HDAC6 levels and decreased IRS1 levels. In-vivo inhibition of H19 led to significant increase in HDAC6 levels and this was associated with a decrease in IRS1 levels in the skeletal muscle.ConclusionsOur results suggest a critical role for the lncRNA H19-HDAC6 axis in regulating IRS1 levels in the skeletal muscle during diabetes and therefore restoring normal H19 levels might hold a therapeutic potential for the management of aberrant skeletal muscle physiology during insulin resistance and type 2 diabetes.

Mediterranean Spur-Thighed Tortoises (Testudo graeca) Have Optimal Speeds at Which They Can Minimise the Metabolic Cost of Transport, on a Treadmill.

Tortoises are famed for their slow locomotion, which is in part related to their herbivorous diet and the constraints imposed by their protective shells. For most animals, the metabolic cost of transport (CoT) is close to the value predicted for their body mass. Testudines appear to be an exception to this rule, as previous studies indicate that, for their body mass, they are economical walkers. The metabolic efficiency of their terrestrial locomotion is explainable by their walking gait biomechanics and the specialisation of their limb muscle physiology, which embodies a predominance of energy-efficient slow-twitch type I muscle fibres. However, there are only two published experimental reports of the energetics of locomotion in tortoises, and these data show high variability. Here, Mediterranean spur-thighed tortoises (Testudo graeca) were trained to walk on a treadmill. Open-flow respirometry and high-speed filming were simultaneously used to measure the metabolic cost of transport and to quantify limb kinematics, respectively. Our data support the low cost of transport previously reported and demonstrate a novel curvilinear relationship to speed in Testudines, suggesting tortoises have an energetically optimal speed range over which they can move in order to minimise the metabolic cost of transport.

Distinctive physiological muscle synergy patterns define the Box and Block Task execution as revealed by electromyographic features.

Stroke survivors experience muscular pattern alterations of the upper limb that decrease their ability to perform daily-living activities. The Box and Block test (BBT) is widely used to assess the unilateral manual dexterity. Although BBT provides insights into functional performance, it returns limited information about the mechanisms contributing to the impaired movement. This study aims at exploring the BBT by means of muscle synergies analysis during the execution of BBT in a sample of 12 healthy participants with their dominant and non-dominant upper limb. Results revealed that: (i) the BBT can be described by 1 or 2 synergies; the number of synergies (ii) does not differ between dominant and non-dominant sides and (iii) varies considering each phase of the task; (iv) the transfer phase requires more synergies. Clinical Relevance- This preliminary study characterizes muscular synergies during the BBT task in order to establish normative patterns that could assist in understanding the neuromuscular demands and support future evaluations of stroke deficits.

Poster 166: Biomechanical Evaluation of Open Bankart and Soft Tissue Bristow Procedures with 10% Glenoid Bone Loss

Objectives:Chronic anterior shoulder instability can be debilitating for a wide number of individuals from the general populations, high level and recreational athletes, laborers and the members of the military. Glenoid bone loss presents a more difficult problem to treat as it negates the positive results that can be achieved with arthroscopic labral repair alone. The optimal procedure for subcritical bone loss of 10% or less is undetermined. In young competitive contact athletes, there is still a high failure rate with arthroscopic procedures. Therefore, the purpose of this study was to biomechanically characterize the effects of soft tissue Bristow (conjoint tendon transfer) and open Bankart repair in a 10% glenoid defect model.Methods:Eight fresh cadavers were studied using a custom shoulder testing system. The rotator cuff muscles were loaded to simulate physiologic muscle conditions. Range of motion, anterior-inferior translation at 60° of external rotation with 20, 30 and 40N of force were tested in scapular and coronal planes. Stiffness and the force required to dislocate in the anterior-inferior direction were also quantified in the coronal plane. 4 different states were examined including: (1) intact capsule (2) Bankart lesion with 10% bone loss, (3) soft tissue Bristow (conjoint tendon transfer), and (4) open Bankart repair. Repeated measures ANOVA with Bonferroni correction was used for statistical analysis.Results:The bony Bankart (injury model) increased range of motion in both the scapular and coronal planes. The conjoint tendon transfer had little effect on range of motion, and the Bankart repair decreased the range of motion to a similar state with that of the pre-injury model. The injury state showed increased translation which was decreased with both the conjoint tendon transfer and the Bankart repair (Figure 1A). The conjoint tendon transfer shifts the humeral head posteriorly in 0° and 30° of external rotation in the scapular plane. There was no difference in stiffness during dislocation between conjoint tendon transfer and Bankart repair (Figure 1B).Conclusions:Both the soft tissue Bristow and the open Bankart repair were noted to decrease anterior translation in this shoulder instability model. Both open repair models significantly decreased anterior translation and are valid surgical options for the treatment of instability with 10% glenoid bone loss. Surgically, an open Bankart repair is more anatomic and may be the preferred technique.

Human Tissue-Engineered Skeletal Muscle: A Tool for Metabolic Research.

Skeletal muscle is now regarded as an endocrine organ based on its secretion of myokines and exerkines, which, in response to metabolic stimuli, regulate the crosstalk between the skeletal muscle and other metabolic organs in terms of systemic energy homeostasis. This conceptual basis of skeletal muscle as a metabolically active organ has provided insights into the potential role of physical inactivity and conditions altering muscle quality and quantity in the development of multiple metabolic disorders, including insulin resistance, obesity, and diabetes. Therefore, it is important to understand human muscle physiology more deeply in relation to the pathophysiology of metabolic diseases. Since monolayer cell lines or animal models used in conventional research differ from the pathophysiological features of the human body, there is increasing need for more physiologically relevant in vitro models of human skeletal muscle. Here, we introduce recent studies on in vitro models of human skeletal muscle generated from adult myogenic progenitors or pluripotent stem cells and summarize recent progress in the development of three-dimensional (3D) bioartificial muscle, which mimics the physiological complexity of native skeletal muscle tissue in terms of maturation and functionality. We then discuss the future of skeletal muscle 3D-organoid culture technology in the field of metabolic research for studying pathological mechanisms and developing personalized therapeutic strategies.

Translational Significance of the LINE-1 Jumping Gene in Skeletal Muscle.

Retrotransposons are gene segments that proliferate in the genome, and the Long INterspersed Element 1 (LINE-1 or L1) retrotransposon is active in humans. Although older mammals show enhanced skeletal muscle L1 expression, exercise generally reverses this trend. We hypothesize skeletal muscle L1 expression influences muscle physiology, and additional innovative investigations are needed to confirm this hypothesis.

The State of the Art of Piezo1 Channels in Skeletal Muscle Regeneration

Piezo1 channels are highly mechanically-activated cation channels that can sense and transduce the mechanical stimuli into physiological signals in different tissues including skeletal muscle. In this focused review, we summarize the emerging evidence of Piezo1 channel-mediated effects in the physiology of skeletal muscle, with a particular focus on the role of Piezo1 in controlling myogenic precursor activity and skeletal muscle regeneration and vascularization. The disclosed effects reported by pharmacological activation of Piezo1 channels with the selective agonist Yoda1 indicate a potential impact of Piezo1 channel activity in skeletal muscle regeneration, which is disrupted in various muscular pathological states. All findings reported so far agree with the idea that Piezo1 channels represent a novel, powerful molecular target to develop new therapeutic strategies for preventing or ameliorating skeletal muscle disorders characterized by an impairment of tissue regenerative potential.

Breathing, (S)Training and the Pelvic Floor-A Basic Concept.

Background: The current scientific literature is inconsistent regarding the potential beneficial or deleterious effects of high-intensity physical activities on the pelvic floor (PF) in women. So far, it has not been established with certainty whether disparate breathing mechanisms may exert short- or long-term influence on the PF function in this context, although based on the established physiological interrelationship of breathing with PF activation, this seems plausible. Objective: To propose a basic concept of the influence of different breathing patterns on the PF during strenuous physical efforts. Methodical approaches: Review of the recent literature, basic knowledge of classical western medicine regarding the principles of muscle physiology and the biomechanics of breathing, additional schematic illustrations, and magnetic resonance imaging (MRI) data corroborate the proposed concept and exemplify the consequences of strenuous efforts on the PF in relation to respective breathing phases. Conclusion: The pelvic floor muscles (PFMs) physiologically act as expiratory muscles in synergy with the anterolateral abdominal muscles, contracting during expiration and relaxing during inspiration. Obviously, a strenuous physical effort requires an expiratory motor synergy with the PFM and abdominal muscles in a co-contracted status to train the PFM and protect the PF against high intra-abdominal pressure (IAP). Holding breath in an inspiratory pattern during exertion stresses the PF because the high IAP impinges on the relaxed, hence insufficiently protected, PFMs. It seems conceivable that such disadvantageous breathing, if performed regularly and repeatedly, may ultimately cause PF dysfunction. At any rate, future research needs to take into account the respective breathing cycles during measurements and interventions addressing PFM function.

Long-distance transit alters liver and skeletal muscle physiology of beef cattle

Transportation of cattle is necessary but negatively impacts animal health and production efficiency. To gain a better understanding of the physiological responses to long-distance road transit, 36 crossbred beef steers (324 ± 36 kg) were randomly assigned to treatments (n = 12 steers/treatment): no transit and ad libitum access to feed and water (CON), no transit but deprived of feed and water for 18 h (DEPR), or road transit and no access to feed or water for 18 h (1 790 km; TRANS). Blood, liver, and muscle (longissimus dorsi) samples were collected pre- and post-treatment for analysis of blood metabolites, blood leukocyte profiles, blood markers of oxidative stress, and tissue antioxidant enzyme activity. Additionally, discovery-based metabolomics and proteomics analyses were performed on tissue samples collected immediately post-treatment (d 1). Data (except for omics) were analyzed using ProcMixed of SAS 9.4 with the fixed effect of treatment and steer as the experimental unit. Omics data were analyzed using MetaboAnalyst; metabolites and proteins of interest were identified based on a fold change threshold of 1.20 and t-test P-value of 0.10. On d 1, percent of pretreatment BW and DM intake were least for TRANS steers (P ≤ 0.06). Percent of pretreatment BW remained lesser for TRANS steers on d 8 (P = 0.05). Serum haptoglobin was greatest for TRANS steers immediately post-treatment (P = 0.02). Additionally, TRANS steers exhibited the greatest increase in the neutrophil to lymphocyte ratio and serum non-esterified fatty acids during the treatment period (P < 0.01), indicating TRANS steers experienced a more robust inflammatory and neuroendocrine response. Immediately post-treatment, liver superoxide dismutase activity tended to be greatest for both DEPR and TRANS (P = 0.07) while muscle superoxide dismutase activity was only greatest for TRANS (P = 0.02), suggesting TRANS steers may have experienced more oxidative stress due to the additional physical effort required to stand and maintain balance during transit. The abundance of several proteins (alpha-2-HS-glycoprotein) and metabolites (lactate, citrate, tri-hydroxybutyric acid, and leucine) associated with energy metabolism were altered in the liver and muscle of TRANS. The differential responses for DEPR versus TRANS steers indicate muscle plays an important role in how cattle respond to and recover from transportation stress.

226-LB: Genetic Variation of Human Myokine Signaling Is Dominated by Biologic Sex and Sex Hormones

Skeletal muscle physiology is a critical determinant and therapeutic target for type 2 diabetes. Proteins secreted from skeletal muscle, termed myokines, allow the muscle to communicate with other key metabolic organs and several have been established as causal drivers of processes such as exercise and lipid metabolism. Yet, the genetic architecture, regulation, and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. In this study, we performed the first targeted genetic survey of myokine gene regulation and cross-tissue signaling in 310 humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion. Estrogen signaling specifically in muscle showed striking enrichments with myokines, independent of sex-specific signaling. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice lacking estrogen receptor α (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes, and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs. This study is currently available on bioRxiv: https://www.biorxiv.org/content/10.1101/2022.01.20.477045v1 Disclosure C. Van: None. M. Seldin: None.

Commentary: The electromyographic analysis of orbicularis oculi muscle in epiphora.

The simplest description of functional epiphora is “epiphora in the presence of a patent lacrimal drainage system, absence of any demonstrable anatomical abnormality, and absence of alternative etiology.”[1] It is a complex and underdiagnosed entity. Jones, in 1957, suggested dysfunctions of the lacrimal pump as the major aberration in functional epiphora.[2] Ali et al.,[3] in 2020, presented a new theory of lacrimal pump functions based on their anatomical, ultrastructural, and immunohistochemical studies of the Horner–Duverney (HD) muscle. The diagnosis of functional epiphora is by a series of examinations and imaging to exclude other causes. In essence, it is a diagnosis of exclusion. Hence, a careful clinical examination along with magnetic resonance dacryocystography or dacryoscintigraphy are helpful.[4] The data on the use of electromyography (EMG) and its characteristics in such cases is evolving. The present study succinctly described the electromyographic response of the deeper heads of the orbicularis oculi muscle using the motor unit potential (MUP) analysis.[5] A statistically significant change in the amplitude, duration, number of phases, turns, and rise time were noted between the functional epiphora cohort and normal volunteers. The EMG was suggestive of a neurogenic origin of lacrimal pump weakness in patients with functional epiphora. Apart from the earlier known motor innervation by the branches of the facial nerve, recent other explorations have pointed to the presence of an extensive network of additional sensory, sympathomimetic, and parasympathetic innervation of the HD muscle.[3] Hence, the EMG needs to be further explored. Although the present study had several limitations, including difficulties with the not very conclusive results, it is nevertheless an excellent strategy to begin answering the proposed research query. To what extent can an EMG help appreciate the complex physiology of the HD muscle is yet to be deciphered. Although EMG partly enhances our understanding of the orbicularis oculi behavior in different clinical settings, it does not directly assess the lacrimal pump mechanisms of tear flow. Besides, it is unhelpful to assess other mechanisms in tear flow dynamics such as capillary action, gravity, and pressure gradient. At present, EMG of the HD muscle has limited clinical worth and, at best, can be of adjunctive value. However, its utility as a research tool has the potential to further our understanding of the lacrimal pump. Financial disclosure Mohammad Javed Ali receives royalties from Springer for the textbook “Principles and Practice of Lacrimal Surgery,” “Atlas of Lacrimal Drainage Disorders,” and “Video Atlas of Lacrimal Surgery.”

O-GlcNAcylation: The Underestimated Emerging Regulators of Skeletal Muscle Physiology.

O-GlcNAcylation is a highly dynamic, reversible and atypical glycosylation that regulates the activity, biological function, stability, sublocation and interaction of target proteins. O-GlcNAcylation receives and coordinates different signal inputs as an intracellular integrator similar to the nutrient sensor and stress receptor, which target multiple substrates with spatio-temporal analysis specifically to maintain cellular homeostasis and normal physiological functions. Our review gives a brief description of O-GlcNAcylation and its only two processing enzymes and HBP flux, which will help to better understand its physiological characteristics of sensing nutrition and environmental cues. This nutritional and stress-sensitive properties of O-GlcNAcylation allow it to participate in the precise regulation of skeletal muscle metabolism. This review discusses the mechanism of O-GlcNAcylation to alleviate metabolic disorders and the controversy about the insulin resistance of skeletal muscle. The level of global O-GlcNAcylation is precisely controlled and maintained in the “optimal zone”, and its abnormal changes is a potential factor in the pathogenesis of cancer, neurodegeneration, diabetes and diabetic complications. Although the essential role of O-GlcNAcylation in skeletal muscle physiology has been widely studied and recognized, it still is underestimated and overlooked. This review highlights the latest progress and potential mechanisms of O-GlcNAcylation in the regulation of skeletal muscle contraction and structural properties.

Sirt2 positively regulates muscle regeneration after Notexin-induced muscle injury

Sirt2 regulates various biological processes by deacetylating target genes. Despite roles in regulating proliferation, cell cycle, and glucose metabolism, which are closely associated with skeletal muscle physiology, Sirt2 functions in this tissue remain unclear. In this study, genetic deletion of Sirt2 delayed muscle regeneration after Notexin-induced muscle injury. Gene expressions of myogenic regulatory factors, including Myf5, MyoD, and Myogenin, and cell cycle regulators, such as cyclin D1 and CDK2, were repressed in Sirt2 knockout mice after injury. Also, Sirt2 knockout mice presented muscle atrophy after muscle injury which is associated with the down-regulation of anabolic signaling and the up-regulation of catabolic signaling, in particular, increased atrogin1 transcriptional expression. Thus, Sirt2 positively regulated skeletal muscle regeneration after muscle injury by regulating transcriptional expression involved in myogenesis, cell cycle, and anabolic and catabolic signaling. Based on the in vivo analyses, Sirt2 could function as an interventional therapeutic for chronic myopathy, which is characterized by impaired muscle regeneration and muscle atrophy.