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Wiley Interdisciplinary Reviews.... Jan 2020Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue,... (Review)
Review
Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The "omics" revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross-talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems-level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Cellular Models.
Topics: Animals; Biophysical Phenomena; Extracellular Matrix; Humans; Models, Biological; Muscle Contraction; Muscle, Skeletal; Muscular Diseases; Neuromuscular Junction; Satellite Cells, Skeletal Muscle; Synapses
PubMed: 31407867
DOI: 10.1002/wsbm.1462 -
Frontiers in Endocrinology 2020Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although... (Review)
Review
Hormones are largely responsible for the integrated communication of several physiological systems responsible for modulating cellular growth and development. Although the specific hormonal influence must be considered within the context of the entire endocrine system and its relationship with other physiological systems, three key hormones are considered the "anabolic giants" in cellular growth and repair: testosterone, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these anabolic hormones, glucocorticoids, mainly cortisol must also be considered because of their profound opposing influence on human skeletal muscle anabolism in many instances. This review presents emerging research on: (1) Testosterone signaling pathways, responses, and adaptations to resistance training; (2) Growth hormone: presents new complexity with exercise stress; (3) Current perspectives on IGF-I and physiological adaptations and complexity these hormones as related to training; and (4) Glucocorticoid roles in integrated communication for anabolic/catabolic signaling. Specifically, the review describes (1) Testosterone as the primary anabolic hormone, with an anabolic influence largely dictated primarily by genomic and possible non-genomic signaling, satellite cell activation, interaction with other anabolic signaling pathways, upregulation or downregulation of the androgen receptor, and potential roles in co-activators and transcriptional activity; (2) Differential influences of growth hormones depending on the "type" of the hormone being assayed and the magnitude of the physiological stress; (3) The exquisite regulation of IGF-1 by a family of binding proteins (IGFBPs 1-6), which can either stimulate or inhibit biological action depending on binding; and (4) Circadian patterning and newly discovered variants of glucocorticoid isoforms largely dictating glucocorticoid sensitivity and catabolic, muscle sparing, or pathological influence. The downstream integrated anabolic and catabolic mechanisms of these hormones not only affect the ability of skeletal muscle to generate force; they also have implications for pharmaceutical treatments, aging, and prevalent chronic conditions such as metabolic syndrome, insulin resistance, and hypertension. Thus, advances in our understanding of hormones that impact anabolic: catabolic processes have relevance for athletes and the general population, alike.
Topics: Adaptation, Physiological; Animals; Exercise; Growth Hormone; Growth and Development; Humans; Hydrocortisone; Muscle, Skeletal; Somatomedins; Testosterone
PubMed: 32158429
DOI: 10.3389/fendo.2020.00033 -
Cells May 2023Turner syndrome (TS), a genetic disorder due to incomplete dosage compensation of X-linked genes, affects multiple organ systems, leading to hypogonadotropic... (Review)
Review
Turner syndrome (TS), a genetic disorder due to incomplete dosage compensation of X-linked genes, affects multiple organ systems, leading to hypogonadotropic hypogonadism, short stature, cardiovascular and vascular abnormalities, liver disease, renal abnormalities, brain abnormalities, and skeletal problems. Patients with TS experience premature ovarian failure with a rapid decline in ovarian function caused by germ cell depletion, and pregnancies carry a high risk of adverse maternal and fetal outcomes. Aortic abnormalities, heart defects, obesity, hypertension, and liver abnormalities, such as steatosis, steatohepatitis, biliary involvement, liver cirrhosis, and nodular regenerative hyperplasia, are commonly observed in patients with TS. The gene plays a crucial role in short stature and abnormal skeletal phenotype in patients with TS. Abnormal structure formation of the ureter and kidney is also common in patients with TS, and a non-mosaic 45,X karyotype is significantly associated with horseshoe kidneys. TS also affects brain structure and function. In this review, we explore various phenotypic and disease manifestations of TS in different organs, including the reproductive system, cardiovascular system, liver, kidneys, brain, and skeletal system.
Topics: Humans; Female; Pregnancy; Turner Syndrome; Heart Defects, Congenital; Primary Ovarian Insufficiency; Karyotype; Karyotyping; Liver Diseases; Short Stature Homeobox Protein
PubMed: 37408200
DOI: 10.3390/cells12101365 -
International Journal of Medical... 2021Bone is an active tissue, being constantly renewed in healthy individuals with participation of the immune system to a large extent. Any imbalance between the processes... (Review)
Review
Bone is an active tissue, being constantly renewed in healthy individuals with participation of the immune system to a large extent. Any imbalance between the processes of bone formation and bone resorption is linked to various inflammatory bone diseases. The immune system plays an important role in tissue formation and bone resorption. Recently, many studies have demonstrated complex interactions between the immune and skeletal systems. Both of immune cells and cytokines contribute to the regulation of bone homeostasis, and bone cells, including osteoblasts, osteoclasts, osteocytes, also influence the cellular functions of immune cells. These crosstalk mechanisms between the bone and immune system finally emerged, forming a new field of research called osteoimmunology. Therefore, the immune microenvironment is crucial in determining the speed and outcome of bone healing, repair, and regeneration. In this review, we summarise the role of the immune microenvironment in bone regeneration from the aspects of immune cells and immune cytokines. The elucidation of immune mechanisms involved in the process of bone regeneration would provide new therapeutic targets for improving the curative effects of bone injury treatment.
Topics: Animals; Bone Regeneration; Bone Remodeling; Bone and Bones; Cellular Microenvironment; Humans; Immune System; Osteoblasts; Osteoclasts; Osteocytes
PubMed: 34790042
DOI: 10.7150/ijms.61080 -
Nature Reviews. Cardiology Jun 2021Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments. HFpEF is arguably the greatest unmet medical need in cardiovascular disease. Although HFpEF was initially considered to be a haemodynamic disorder characterized by hypertension, cardiac hypertrophy and diastolic dysfunction, the pandemics of obesity and diabetes mellitus have modified the HFpEF syndrome, which is now recognized to be a multisystem disorder involving the heart, lungs, kidneys, skeletal muscle, adipose tissue, vascular system, and immune and inflammatory signalling. This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. However, new animal models involving both haemodynamic and metabolic disease, and increasing efforts to examine human pathophysiology, are revealing new signalling pathways and potential therapeutic targets. In this Review, we discuss the cellular and molecular pathobiology of HFpEF, with the major focus being on mechanisms relevant to the heart, because most research has focused on this organ. We also highlight the involvement of other important organ systems, including the lungs, kidneys and skeletal muscle, efforts to characterize patients with the use of systemic biomarkers, and ongoing therapeutic efforts. Our objective is to provide a roadmap of the signalling pathways and mechanisms of HFpEF that are being characterized and which might lead to more patient-specific therapies and improved clinical outcomes.
Topics: Heart Failure; Humans; Stroke Volume
PubMed: 33432192
DOI: 10.1038/s41569-020-00480-6 -
Physiology (Bethesda, Md.) Jan 2020The generation of action potentials in intramuscular motor and sensory axons in response to an imposed external current source can evoke muscle contractions and elicit... (Review)
Review
The generation of action potentials in intramuscular motor and sensory axons in response to an imposed external current source can evoke muscle contractions and elicit widespread responses throughout the nervous system that impact sensorimotor function. The benefits experienced by individuals exposed to several weeks of treatment with electrical stimulation of muscle suggest that the underlying adaptations involve several physiological systems, but little is known about the specific changes elicited by such interventions.
Topics: Action Potentials; Adaptation, Physiological; Electric Stimulation; Electromyography; Humans; Muscle Contraction; Muscle, Skeletal; Muscular Diseases
PubMed: 31799910
DOI: 10.1152/physiol.00015.2019 -
EBioMedicine Nov 2019As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and... (Review)
Review
As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. The disease burden of these pathologies emphasizes the need for a better understanding of the underlying mechanisms. Skeletal muscle has emerged as a potent regulator of immune system function. As such, skeletal muscle might be the central integrator between sarcopenia and immune senescence in an aging biological system. Therapeutic approaches targeting skeletal muscle might be able to restore both muscle and immune system function. In this review, we therefore outline the current - however still fragmentary - knowledge about the potential communication pathways of muscle and immune system, how they are affected by aging of skeletal muscle and discuss possible treatment strategies. The review intends to be hypothesis-generating and should thereby stimulate further research in this important scientific field.
Topics: Aging; Cell Communication; Humans; Immune System; Muscle, Skeletal; Risk Factors; Sarcopenia
PubMed: 31662290
DOI: 10.1016/j.ebiom.2019.10.034 -
International Journal of Molecular... Aug 2022Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in... (Review)
Review
Functional status is considered the main determinant of healthy aging. Impairment in skeletal muscle and the cardiovascular system, two interrelated systems, results in compromised functional status in aging. Increased oxidative stress and inflammation in older subjects constitute the background for skeletal muscle and cardiovascular system alterations. Aged skeletal muscle mass and strength impairment is related to anabolic resistance, mitochondrial dysfunction, increased oxidative stress and inflammation as well as a reduced antioxidant response and myokine profile. Arterial stiffness and endothelial function stand out as the main cardiovascular alterations related to aging, where increased systemic and vascular oxidative stress and inflammation play a key role. Physical activity and exercise training arise as modifiable determinants of functional outcomes in older persons. Exercise enhances antioxidant response, decreases age-related oxidative stress and pro-inflammatory signals, and promotes the activation of anabolic and mitochondrial biogenesis pathways in skeletal muscle. Additionally, exercise improves endothelial function and arterial stiffness by reducing inflammatory and oxidative damage signaling in vascular tissue together with an increase in antioxidant enzymes and nitric oxide availability, globally promoting functional performance and healthy aging. This review focuses on the role of oxidative stress and inflammation in aged musculoskeletal and vascular systems and how physical activity/exercise influences functional status in the elderly.
Topics: Aged; Aged, 80 and over; Antioxidants; Exercise; Humans; Inflammation; Muscle, Skeletal; Oxidative Stress
PubMed: 35955849
DOI: 10.3390/ijms23158713 -
Endocrine Reviews May 2022Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies... (Review)
Review
Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.
Topics: Animals; Anti-Obesity Agents; Genetic Therapy; Homeostasis; Humans; Obesity; Weight Loss
PubMed: 35552683
DOI: 10.1210/endrev/bnab034 -
Nature Communications Dec 2021Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal...
Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal muscle tissues. In general, AAV vectors are used for in vivo delivery, but AAV injections cannot be repeated because of neutralization antibodies. Here we report a chemically defined lipid nanoparticle (LNP) system which is able to deliver Cas9 mRNA and sgRNA into skeletal muscle by repeated intramuscular injections. Although the expressions of Cas9 protein and sgRNA were transient, our LNP system could induce stable genomic exon skipping and restore dystrophin protein in a DMD mouse model that harbors a humanized exon sequence. Furthermore, administration of our LNP via limb perfusion method enables to target multiple muscle groups. The repeated administration and low immunogenicity of our LNP system are promising features for a delivery vehicle of CRISPR-Cas9 to treat skeletal muscle disorders.
Topics: Animals; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Disease Models, Animal; Dystrophin; Exons; Gene Editing; Genetic Therapy; Humans; Liposomes; Mice; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Nanoparticles; Neuromuscular Diseases; RNA, Messenger
PubMed: 34880218
DOI: 10.1038/s41467-021-26714-w