Muscle 2-Volume Set

List of Contributors

Acknowledgments

VOLUME 1

Part I: Introduction

Chapter 1. An Introduction to Muscle

Cardiac Muscle

Skeletal Muscle

Smooth Muscle

Common Molecular Mechanisms

Summary

Chapter 2. A History of Muscle

Introduction

Early Observations

Animal Spirits and the Vital Force

Electrical Activation

Energy Utilization: Work and Heat

Energy Production: Metabolism

Contractile Proteins

The Sliding-Filament Hypothesis

Calcium, Excitation–Contraction Coupling, Relaxation

Skeletal, Cardiac, and Smooth Muscle

Conclusion

REFERENCES

Part II: Cardiac Muscle

Section A: Basic Physiology

Chapter 3. Cardiac Myocyte Specification and Differentiation

Early Fate Decisions in Commitment of Mesoderm to the Cardiac Muscle Lineage

Cardiac Progenitors Arise from Two Molecularly Distinct “Heart Fields”

Differentiation of Cardiac Progenitors into Functional Myocytes

Conclusions

REFERENCES

Chapter 4. Transcriptional Control of Cardiogenesis

Overview of Transcription Factors Necessary for Heart Development

Transcriptional Regulation of Cardiac Morphogenesis

Transcriptional Regulation of Cardiac Conduction System Development

Transcriptional Regulation of Cardiomyocyte Proliferation

Summary and Perspectives

Acknowledgments

REFERENCES

Chapter 5. Cardiomyocyte Ultrastructure

Introduction

Myocyte Architecture

Non-Myocyte Tissue Compartment

Regional Variation in Structure

REFERENCES

Chapter 6. Overview of Cardiac Muscle Physiology

Introduction

The Cardiac Pump

Regulation of the Cardiac Pump

Basis for the Cardiac Output Changes During Exercise

Bibliography

Chapter 7. Ionic Fluxes and Genesis of the Cardiac Action Potential

Ionic Flux in Cardiomyocytes

Membrane Transporters

Action Potential Genesis

Action Potential Propagation – Electrical Communication

Acknowledgments

REFERENCES

Chapter 8. G-Protein-Coupled Receptors in the Heart

Introduction

Overview of G-Protein-Coupled Receptor Signaling

Cardiac G-Protein-Coupled Receptors

The Future of GPCR Drug Targeting

REFERENCES

Chapter 9. Receptor Tyrosine Kinases in Cardiac Muscle

Overview of RTK Biology

RTK Expression and Function in Cardiac Myocytes

RTK Transactivation by GPCR

Conclusion: Toward Integrative Signaling Approaches

REFERENCES

Chapter 10. Communication in the Heart: Cardiokines as Mediators of a Molecular Social Network

Cardiokines and the Molecular Social Network of Cell Communication

Mechanisms of Secretory Protein Synthesis, Processing, and Secretion

ANP, The Archetype Cardiokine

Novel Autocrine and Paracrine Signaling Proteins in the Heart

Conclusions

Acknowledgments

REFERENCES

Chapter 11. Calcium Fluxes and Homeostasis

Introduction

Intracellular and Extracellular Ca2+ Concentrations During Diastole

Surface Membrane Ca2+ Efflux Mechanisms

Sarcoplasmic Reticulum (SR) Ca2+ Storage and Release

Mitochondrial Ca2+ Regulation

Ca2+, Mitochondria, Cell Death, and Contractile Dysfunction

Ca2+ and Transcriptional Regulation and Hypertrophy

Ca2+/CaM-CAMKII-HDAC Pathway

Ca2+-CaM-Calcineurin-NFAT Pathway

Ca2+ Flux Balance is Ca2+ Homeostasis

Physiological Regulation of Ca2+ to Control Cardiac Contractility

Dysregulated Ca2+ and Cardiac Dysfunction in Heart Disease

REFERENCES

Chapter 12. Excitation–Contraction Coupling in the Heart

Introduction

Excitation at the Sarcolemma

Ca2+ Release from the Sarcoplasmic Reticulum – Myocyte Contraction

Cardiomyocyte Relaxation

The RyR2 Macromolecular Complex and its Regulation

Regulation of EC Coupling by β-Adrenergic Stimulation

REFERENCES

Chapter 13. Role of Sarcomeres in Cellular Tension, Shortening, and Signaling in Cardiac Muscle

Introduction

Cardiac Sarcomeres Have Distinct Structures and Functions

State Changes in Cardiac Sarcomeres and the Heart Beat

Control of Contractility at the Level of Sarcomeric Proteins

Conclusions

Acknowledgments

REFERENCES

Chapter 14. Cardiovascular Mechanotransduction

Introduction

Acute Physiological Adaptations to Mechanical Stress

Overview and Localization of Mechanosensitive Structures

Mechanotransduction Initiated at the Sarcomere

Fibroblast–Cardiomyocyte Crosstalk

Conclusion

Acknowledgments

REFERENCES

Chapter 15. Cardiomyocyte Metabolism: All Is in Flux

Fuel Metabolism in Perspective

Mitochondria and the Dynamics of Metabolism in the Heart

The Highways of Energy Transfer

Tracing Metabolic Pathways ex vivo and in vivo

Genetic Models for the Elucidation of Cardiac Metabolism

Major Energy-Providing Substrates

Metabolic Remodeling

Conclusions

Acknowledgments

REFERENCES

Chapter 16. Transcriptional Control of Striated Muscle Mitochondrial Biogenesis and Function

General Overview of Mitochondrial Function and Biogenesis

Transcriptional Regulatory Circuitry Involved in Mitochondrial Biogenesis

Transcriptional Regulatory Circuitry Orchestrating Mitochondrial Biogenesis: The PGC-1 Coactivators

Defining the Requisite Role of Transcriptional Regulatory Factors in Striated Muscle Mitochondrial Biology and Physiology: Lessons from Gene-Targeted Mice

Implications for Myocardial Disease

Acknowledgments

REFERENCES

Chapter 17. Mitochondrial Morphology and Function

Relationships with Other Cellular Structures

Mitochondrial Compartments

Mitochondrial Shape and Tethering to the SR: Molecular Determinants

Energy-Linked Functions

Mitochondrial Generation of Reactive Oxygen Species

The Mitochondrial Permeability Transition Pore

Acknowledgments

REFERENCES

Chapter 18. Genetics and Genomics in Cardiovascular Gene Discovery

What is the Genetic Paradigm and Why is Genomics Indispensible?

The Structure and Conservation of the Human Genome

The Functions Encoded in the Human Genome

The Nature of Sequence Variation in Man: From Individual Genes to Whole Genomes

Mapping a Disease Locus by Linkage, Association, and Dosage Variants

Cardiovascular Genetics and Genomics: A Status Report Using Key Examples

REFERENCES

Chapter 19. Cardiovascular Proteomics: Assessment of Protein Post-Translational Modifications

Introduction

Technical Heart of Proteomics: Analytical Separation, Mass Spectrometry and Bioinformatics

Tackling the Subproteomes

Site-Specific Quantification of Protein PTMs by MRM

Conclusions

Acknowledgments

REFERENCES

Section B: Adaptations and Response

Chapter 20. Adaption and Responses: Myocardial Innervations and Neural Control

Introduction

Regulation of Brainstem Autonomic Function

Myocardial Innervations from Brainstem to Organ: Efferent Parasympathetic Innervation

Myocardial Innervations from Brainstem to Organ: Efferent Sympathetic Innervation

Myocardial Innervations: Cardiac Afferent Innervation

Integration of Sympatho-Vagal Balance at the Level of the Myocyte

Cardiac Autonomic Control and Cardiovascular Disease

REFERENCES

Chapter 21. Regulation of Cardiac Systolic Function and Contractility

Introduction: What is Contractility?

Measuring Systole

Control of Systole by Altered Loading

Control of Systole by Heart Rate

Post-Translational Regulation of Myofilament Proteins

Conclusion

REFERENCES

Chapter 22. Intracellular Signaling Pathways in Cardiac Remodeling

Concept of Physiological and Pathological Remodeling in Heart

Intracellular Signaling Pathways in Physiological Remodeling (Figure 22.2)

Intracellular Signaling Pathways in Pathological Remodeling

Conclusion

REFERENCES

Chapter 23. Oxidative Stress and Cardiac Muscle

Definition and Intracellular Dynamics of ROS

Physiological Function of ROS

The Role of Oxidative Stress in Mediating Cardiac Diseases and Aging

The Role of Reductive Stress in Mediating Cardiac Diseases

The Role of S-Nitrosylation and Nitrosative Stress in Mediating Cardiac Disease

Concluding Remarks

REFERENCES

Chapter 24. Physiologic and Molecular Responses of the Heart to Chronic Exercise

Physiologic Accommodations to Chronic Exercise

Can Physiologic Cardiac Adaptation Lead To Cardiac Pathology?

Molecular Remodeling in Physiologic Hypertrophy

Gene Expression

Myocardial Energetics and Mitochondrial Function

Nodal Signaling Pathways

Role of Non-Cardiocyte (Paracrine) Signaling Mechanisms

Future Directions/Therapeutic Targets

REFERENCES

Chapter 25. Epigenetics in Cardiovascular Biology

Introduction to Epigenetics

Epigenetics and Heart Development

Epigenetic Modifications in Cardiovascular Disease

Present and Future Prospects for Epigenetic Therapy in Cardiovascular Disease

REFERENCES

Chapter 26. Cardiac MicroRNAs

Introduction

MiRNA Biogenesis

miRNA Function in the Heart

MiRNA Dysregulation during Cardiac Disease

Therapeutic Regulation miRNAs

Plasma Detection of miRNAs as Novel Biomarkers for Cardiovascular Disease

Concluding Remarks

REFERENCES

Chapter 27. Protein Quality Control in Cardiomyocytes

Introduction

Chaperones in PQC

The Ubiquitin-Proteasome System

ER-Associated PQC and Cardiac Dysfunction

PQC Inadequacy in Cardiac Remodeling and Failure

REFERENCES

Chapter 28. Cardioprotection

Mechanisms of Muscle Injury and Cell Death

Cardioprotection Induced by Preconditioning and Postconditioning

Cardioprotective Agents and Strategies

Central Role of Mitochondria in Myocardial Cell Survival

Translation to the Clinic

Summary and Future Directions

REFERENCES

Chapter 29. Cardiac Fibrosis: Cellular and Molecular Determinants

Introduction

The Role of Cardiac Fibroblasts in the Myocardium

The Origin of Cardiac Fibroblasts

Development of Fibrosis

Clinical Manifestations of Cardiac Fibrosis

Treatment of Cardiac Fibrosis

Conclusion

REFERENCES

Chapter 30. Autophagy in Cardiac Physiology and Disease

Cardiac Growth and Plasticity

Autophagy: Cellular Cannibalization

Molecular Anatomy of Autophagy

Pathways Governing Autophagy

Functional Consequences of Autophagic Flux in the Heart

Autophagy in Human Cardiovascular Disease

Cardiac Autophagy as a Therapeutic Target

Summary and Perspective

Acknowledgments

REFERENCES

Chapter 31. Programmed Cardiomyocyte Death in Heart Disease

Introduction: The Role of Programmed Cell Death in Health and Disease

Different Mechanisms of Programmed Cell Death in the Heart

Programmed Cell Death in Heart Disease

Genetic and Pharmacological Inhibition of Programmed Cardiomyocyte Death

REFERENCES

Chapter 32. Wnt and Notch: Potent Regulators of Cardiomyocyte Specification, Proliferation, and Differentiation

Introduction

Cardiac Development: Contribution of Multiple Cell Lineages

Wnt Signaling in Cardiogenesis

Notch Signaling in Cardiogenesis

Conclusions

REFERENCES

Section C: Myocardial Disease

Chapter 33. Congenital Cardiomyopathies

Normal Muscle Structure and Function

Dilated Cardiomyopathy

Hypertrophic Cardiomyopathy

Restrictive Cardiomyopathy

Arrhythmogenic Cardiomyopathy

Left Ventricular Noncompaction

REFERENCES

Chapter 34. Genetics of Congenital Heart Disease

Introduction

T-Box Transcription Factors and Associated Factors: NKX2.5, GATA4, MYH6

Neural Crest Cells and Laterality: TFAP2B, CITED2, ZIC3

Cardiac Outflow Tract Development: Notch Signaling Pathway

Other Genetic Syndromes Caused by Single Gene Defects

REFERENCES

Chapter 35. Mechanisms of Stress-Induced Cardiac Hypertrophy

Introduction

Cardiac Hypertrophy

Biomechanical Stress Signaling and Cardiomyocyte Hypertrophy

Inhibition of Hypertrophy as a Therapeutic Concept

Conclusion

REFERENCES

Chapter 36. Ischemic Heart Disease

Introduction

Pathophysiology of Myocardial Ischemia

Myocardial Infarction

Chronic Ischemic Heart Disease

REFERENCES

Chapter 37. The Pathophysiology of Heart Failure

Introduction and Definitions

Symptoms of Heart Failure

Signs and Radiographic Features of Heart Failure

The Initial Deleterious Event

Neurohormonal Responses to the Initial Deleterious Event

Pathological Left Ventricular Remodeling

Hemodynamic Alterations in Heart Failure

Current Therapy of Heart Failure and Relationship to Pathophysiology

REFERENCES

Chapter 38. The Right Ventricle: Reemergence of the Forgotten Ventricle

Formation and Structure of the Right Ventricle

The Right Ventricle in Pulmonary Hypertension

Adaptive Versus Maladaptive RVH

Sympathetic Activation in PH

Right Ventricular Metabolism in RVH

Diseases of the Right Ventricle

Right Ventricular Infarction

Conclusion

REFERENCES

Chapter 39. Mammalian Myocardial Regeneration

Normal Myocardial Growth and Cell Cycle Activity

The Extent of Endogenous Myocardial Regeneration (Table 39.1)

Cardiac Progenitor Cells

Proliferation of Differentiated Cardiomyocytes

Conclusions

Acknowledgments

REFERENCES

Chapter 40. The Structural Basis of Arrhythmia

Introduction

Anatomy of the Cardiac Conduction System

Structural Basis for Bradyarrhythmias

Structural Basis of Tachyarrhythmias

REFERENCES

Chapter 41. Molecular and Cellular Mechanisms of Cardiac Arrhythmias

Brief Review of Cardiac Cellular and Tissue Electrophysiology

Abnormalities of Impulse Generation

Abnormalities of Impulse Propagation

Cardiac Remodeling

REFERENCES

Chapter 42. Genetic Mechanisms of Arrhythmia

Introduction

The Genetics of Mendelian Arrhythmogenic Disorders

Specific Molecular Mechanisms in Inherited Arrhythmias

REFERENCES

Chapter 43. Infiltrative and Protein Misfolding Myocardial Diseases

Introduction

Protein Misfolding in Cardiac Disease

Pathophysiology

Clinical Manifestations

Diagnosis

Myofibrillar Cardiomyopathies

Amyloid Cardiomyopathies

Therapy and Management

Future Directions

Acknowledgments

REFERENCES

Chapter 44. Cardiac Aging: From Humans to Molecules

Introduction

Macroscopic Structural and Functional Changes

Microscopic Structural and Functional Changes in Isolated Cardiac Muscle and Cell-Culture Systems

Conclusion

REFERENCES

Chapter 45. Adrenergic Receptor Polymorphisms in Heart Failure

Adrenergic Receptor Control of Ventricular Function

Relevance of Adrenergic Receptor Polymorphisms

Cardiac Function in Genetically Altered Mice

Human Studies

Conclusions

REFERENCES

Chapter 46. Cardiac Gene Therapy

Introduction

Gene Delivery

Targets

Clinical Trials

Conclusion

REFERENCES

Chapter 47. Protein Kinases in the Heart: Lessons Learned from Targeted Cancer Therapeutics

Introduction and Background

Her2/Erb-B2

Angiogenesis Inhibitors Targeting VEGF/VEGFRs and PDGFRs

PDGFR

Targeting The PI3-K Pathway

Applications of Kinase Inhibitors to Treat Cardiac Disease – The Other Side of the Coin

REFERENCES

Chapter 48. Cell Therapy for Cardiac Disease

Introduction

Potential Cell Sources

Mechanisms of Action for Cell-Based Therapies

Selected Cell Therapy Clinical Trials

Future Directions

REFERENCES

Chapter 49. Chemical Genetics of Cardiac Regeneration

Introduction

Small-Molecules and Stem Cells: Perfect Partners in an Imperfect World

In Vitro Biological Systems for Cardiac Differentiation

Physiological Screening

Ex Vivo Applications

Targeting The Niche In Vivo

Outlook

Acknowledgments

REFERENCES

Chapter 50. Device Therapy for Systolic Ventricular Failure

Introduction

Implantable Cardioverter-Defibrillators in Heart Failure

Ventricular Dyssynchrony and Heart Failure

Mechanically Assisted Heart Failure: Cellular and Molecular Observations on Reverse Remodeling

The Future: Bridging the Clinical Observations With the Current Understanding of Myocardial Reverse Remodeling

REFERENCES

Chapter 51. Novel Therapeutic Targets and Strategies against Myocardial Diseases

Introduction

G-CSF Therapy for Treatment of Myocardial Infarction

The Role of Tumor-Suppressor Gene Products in Myocardial Pathologies

REFERENCES

VOLUME 2

Part III: Skeletal Muscle

Section A: Basic Physiology

Chapter 52. Skeletal Muscle Development

Introduction

Trunk and Limb Muscles

Head Muscles

Acknowledgments

REFERENCES

Chapter 53. Skeletal Muscle: Architecture of Membrane Systems

The Membrane Systems Involved in Calcium Cycling

Mitochondria

Golgi and Associated Organelles

Pathology of Myofibrils and Membrane Systems

Acknowledgments

REFERENCES

Chapter 54. The Vertebrate Neuromuscular Junction

The Structure of the Junction

The Ultrastructure of the Junction

Clustering of AChR at the Synapse

A Modification to the Agrin Hypothesis: Muscle Pre-Patterning of Receptors

Retrograde Signaling

Structural Biology of the Nerve Terminal Via Electron Microscopy

The Life History of the Neuromuscular Junction

Specificity of Muscle Innervation

Muscle Plasticity Mediated by the NMJ

Some Issues in the Development of Motor Units

The Role of Synaptic Glia

Schwann Cells Play a Role in Repair of Muscle Innervation after Nerve Damage

Acknowledgments

REFERENCES

Chapter 55. Neuromechanical Interactions that Control Muscle Function and Adaptation

Impact of Motor Unit Organization on Muscle Function

Control of Muscle Fiber Diameter and Length

Integration of Active and Passive Elements of Neuromuscular Components, In Vivo

Links Between Neuromechanical and Molecular Mechanisms Underlying Muscle Protein Homeostasis

REFERENCES

Chapter 56. Control of Resting Ca Concentration in Skeletal Muscle

Introduction

Mechanisms for Ca2+ Removal from the Myoplasm of Muscle Cells

Mechanisms for Ca2+ Entry into the Myoplasm in Skeletal Muscle

Methods for Measurements Resting [Ca2+]I in Muscle Cells

Summary

Acknowledgments

REFERENCES

Chapter 57. Skeletal Muscle Excitation–Contraction Coupling

Overview of Steps in Skeletal Muscle Excitation–Contraction Coupling

The Muscle Fiber Action Potential Activates Force Production

A Rise in Myoplasmic [Ca2+] Links Fiber Depolarization to Force Activation

During Steady Experimental Depolarization, Maximum Force Increases Over a Narrow Voltage Range

Large Depolarizations Activate Force Within Milliseconds

Biophysical Characterization of the TT Voltage Sensors

Ca2+ Release Flux from the SR Exhibits an Early Peak and Rapid Inactivation During Depolarization

Molecular Components for T-Tubule Membrane Potential Control of SR Ca2+ Release

The Dihydropyridine Receptor is the Skeletal Muscle TT Voltage Sensor for EC Coupling

The Ryanodine Receptor is the SR Calcium Release Channel

SR Calcium Release Channels can be Studied Directly in Fragmented Systems, but Generally Lack the TT Voltage Sensor

Physiological Mechanism for Activation of the SR Calcium Release Channels in Muscle Fibers

Unitary Ca2+ Release Events: Ca2+ Sparks

Calcium Dependent Contractile Filament Activation

Relaxation

REFERENCES

Chapter 58. The Contractile Machinery of Skeletal Muscle

Sarcomeres are Repeating Units of the Myofibrils

Bands and Filaments

Thin Filament Regulation of Muscle Contraction

The Scaffolding Proteins Give Stability and Elasticity to the Sarcomere

The Z-Line is Involved in Signaling

Faults in the Cross-Striation Alignment

Z-Line Defects in Pathology

Acknowledgments

REFERENCES

Chapter 59. Skeletal Muscle Metabolism

Muscle Metabolism During the Absorptive State

Muscle Metabolism During Fasting

Muscle Metabolism During Exercise

Muscle Insulin Resistance

REFERENCES

Chapter 60. Skeletal Muscle Fiber Types

Diversity of Muscles, Motor Units, and Muscle Fiber Types

Muscle Fiber Types During Development and Aging

Molecular and Functional Differences Among Muscle Fiber Types

Signaling Pathways Involved in Fiber Type Specification and Remodeling

REFERENCES

Section B: Adaptations and Response

Chapter 61. Regulation of Skeletal Muscle Development and Function by microRNAs

microRNA Biogenesis and Function

Skeletal Muscle Without miRNAs

Skeletal Muscle-Specific miRNAs

miR-206 in Skeletal Muscle Function and Disease

miR-1 in Skeletal Muscle Development, Function and Disease

miR-133a in Skeletal Muscle Biology

MyomiRs and Myofiber Type Specification

Other miRNAs in Skeletal Muscle Biology

Therapeutic Implications of miRNAs in Skeletal Muscle Disorders

REFERENCES

Chapter 62. Musculoskeletal Tissue Injury and Repair: Role of Stem Cells, Their Differentiation, and Paracrine Effects

Pathophysiology of Skeletal Muscle Injury

Muscle Stem Cell-Mediated Skeletal Muscle Repair

Muscle Stem Cell-Mediated Cardiac Repair

Muscle Stem Cell-Mediated Bone Repair

Muscle Stem Cell-Mediated Cartilage Repair

Muscle Stem Cell Differentiation into Host Tissue is not a Major Determinant of Success of Repair

Conclusions

Future Directions in Stem Cell Therapy

Acknowledgments

REFERENCES

Chapter 63. Immunological Responses to Muscle Injury

General Characteristics of the Inflammatory Response to Acute Muscle Injury

The Th1 Inflammatory Response in Injured Skeletal Muscle

The Th2 Inflammatory Response in Injured Skeletal Muscle

Inflammatory Cell-Derived Cytokines Have Direct Effects on Muscle Growth and Regeneration

Future Directions

Acknowledgments

REFERENCES

Chapter 64. Skeletal Muscle Adaptation to Exercise

Specificity of Signaling

Adaptation of Skeletal Muscle to Resistance Exercise

Adaptation to Endurance Exercise

Future Directions

Acknowledgments

REFERENCES

Chapter 65. Skeletal Muscle Regeneration

Introduction

Requirement of Satellite Cells in Regeneration

Signaling Pathways in Skeletal Muscle Regeneration

Contribution to Muscle Regeneration by Other Stem Cells

Concluding Remarks

Acknowledgments

REFERENCES

Chapter 66. Skeletal Muscle Dystrophin-Glycoprotein Complex and Muscular Dystrophy

Introduction

The Dystrophin-Glycoprotein Complex in Skeletal Muscle

Dystroglycan: Post-Translational Processing and Function

Sarcoglycan-Sarcospan Subcomplex

Duchenne Muscular Dystrophy and Disruption of the Dystrophin-Glycoprotein Complex

Sarcoglycan-Deficient Limb-Girdle Muscular Dystrophy

Dystroglycanopathies: Limb-Girdle to Congenital Muscular Dystrophy

The Mechanistic Basis of Maintaining Muscle Membrane Integrity

REFERENCES

Section C: Skeletal Muscle Disease

Chapter 67. Statin-Induced Muscle Toxicity: Clinical and Genetic Determinants of Risk

Clinical Aspects

Pharmacokinetic Factors

Pharmacodynamic Factors

REFERENCES

Chapter 68. Myotonic Dystrophy

Genetics and Mechanism of Repeat Expansion

Skeletal Muscle in DM1

Skeletal Muscle in DM2

Cardiac Muscle in DM1

Cardiac Muscle in DM2

Pathophysiology of DM

Therapeutic Implications

REFERENCES

Chapter 69. Facioscapulohumeral Muscular Dystrophy: Unraveling the Mysteries of a Complex Epigenetic Disease

Clinical and Histological Features

Genetic Features

Epigenetic Features

Candidate Genes and Affected Pathways

Therapeutic Strategies

Outlook and Future Directions

Acknowledgments

REFERENCES

Chapter 70. ECM-Related Myopathies and Muscular Dystrophies

Introduction

Myopathies of the ECM

Disorders of the Reticular Lamina and Beyond

Other Skeletal Dysplasias

Summary

REFERENCES

Chapter 71. Molecular Pathogenesis of Skeletal Muscle Abnormalities in Marfan Syndrome

Introduction

Increased Activity of TGF-β Signaling in Marfan Syndrome

Functional Role of TGF-β Signaling in Skeletal Muscle

TGF-β Signaling in Skeletal Muscle of Marfan Syndrome (5)

REFERENCES

Chapter 72. Diseases of the Nucleoskeleton

Introduction

Structure and Function of the Nucleoskeleton

Diseases Linked to Defects of the Nucleoskeleton

Pathophysiological Mechanisms?

Conclusions and Perspectives

REFERENCES

Chapter 73. Channelopathies of Skeletal Muscle Excitability

Clinical Phenotypes from Channel Mutations that Alter Sarcolemmal Excitability

Chloride Channel Loss-of-Function Defects Cause Myotonia

Sodium Channel Gain-of-Function Mutations Cause Myotonia Or Periodic Paralysis

Leaky Mutant Sodium Channels Cause Hypokalemic Periodic Paralysis

Calcium Channel Mutations in Hypokalemic Periodic Paralysis

Inward Rectifier Potassium Channel Loss-of-Function Defects in the Andersen–Tawil Syndrome and Thyrotoxic Periodic Paralysis

REFERENCES

Chapter 74. Thick and Thin Filament Proteins: Acquired and Hereditary Sarcomeric Protein Diseases

Introduction

Altered Myosin and Actin Protein Expression

Hereditary Thick and Thin Filament Protein Myopathies

Acknowledgments

REFERENCES

Chapter 75. Metabolic and Mitochondrial Myopathies

Muscle Fat Metabolism and Disorders (Figure 75.1)

Muscle Carbohydrate Metabolism and Disorders (Figure 75.2)

Mitochondrial Myopathies

REFERENCES

Section D: Therapeutics

Chapter 76. Gene Therapy of Skeletal Muscle Disorders Using Viral Vectors

Introduction

Gene Therapy Vectors and Skeletal Muscle Transduction

Gene Therapy of the Muscular Dystrophies

Conclusions

Acknowledgments

REFERENCES

Chapter 77. Cell-Based Therapies in Skeletal Muscle Disease

Therapeutic Strategies for Muscular Dystrophies

Cell Candidates

Genetic Manipulation for Autologous Cell Therapy

Clinical Trials

Conclusion

Aknowledgments

REFERENCES

Chapter 78. Immunological Components of Genetically Inherited Muscular Dystrophies: Duchenne Muscular Dystrophy and Limb-Girdle Muscular Dystrophy Type 2B

Introduction

Duchenne Muscular Dystrophy

Limb-Girdle Muscular Dystrophy Type 2B

REFERENCES

Chapter 79. Myostatin: Regulation, Function, and Therapeutic Applications

Discovery of Myostatin and its Biological Function as a Negative Regulator of Muscle Mass

Regulation of MSTN Extracellularly by Binding Proteins

Development of MSTN Inhibitors as Potential Therapeutic Agents

Physiological Effects of Targeting MSTN Signaling in Normal and Disease Settings

Conclusions and Speculation

REFERENCES

Chapter 80. Insulin-Like Growth Factor I Regulation and Its Actions in Skeletal Muscle Growth and Repair

Introduction

IGF-I Activity and its Regulation

Regulation of IGF-I Production and Activity

Alternative Splicing

Potential Functions of IGF-I E-Peptides

IGF-I Processing

Targets for Therapy

Risks of IGF-I for Therapy

Current and Emerging Strategies for Therapy

REFERENCES

Chapter 81. Novel Targets and Approaches to Treating Skeletal Muscle Disease

Introduction

Disease Targets

Resealing Muscle Membrane Disruption

Stimulating Muscle Growth

Inflammation and Fibrosis

Calcium and Mitochondrial Dysregulation in Muscle Disease

Gene Correction Strategies

Conclusions

REFERENCES

Part IV: Smooth Muscle

Section A: Basic Physiology

Chapter 82. Development of the Smooth Muscle Cell Lineage

Diversity of the Smooth Muscle Cell Lineage(s)

SMC Progenitors and Stem Cells

Embryologic Origins of Smooth Muscle Cell Lineage

Conclusions and Future Directions

REFERENCES

Chapter 83. Smooth Muscle Myocyte Ultrastructure and Contractility

Introduction

The Contractile Apparatus

The Myosin Motor

Myosin Filaments

Contractile Regulation

Actin

Mechanics and Energetics of Contraction

Architecture and Function of the Sarcoplasmic Reticulum

Mitochondria

Surface Vesicles

Conclusion

Acknowledgments

REFERENCES

Chapter 84. Potassium, Sodium, and Chloride Channels in Smooth Muscle Cells

Introduction

Potassium Channels

Voltage-Sensitive Sodium Channels

Chloride Channels

Perspectives

REFERENCES

Chapter 85. G-Protein-Coupled Receptors in Smooth Muscle

Introduction

G-Protein-Coupled Receptors

G-Protein-Coupled Receptors Involved in the Regulation of Smooth Muscle Cell Function

Pharmacological Regulation of Smooth Muscle Function Through GPCRs

Conclusions

REFERENCES

Chapter 86. Calcium Homeostasis and Signaling in Smooth Muscle

Introduction

Sources of Ca2+ in Smooth Muscle Cells

Ca2+ Clearance Systems

Conclusion

REFERENCES

Chapter 87. Regulation of Smooth Muscle Contraction

Types of Contractile Stimulation

Contractile Signaling Pathways by Target

Organization of Signaling Pathways

Conclusions

REFERENCES

Section B: Heterogeneities

Chapter 88. Heterogeneity of Smooth Muscle

Introduction

Smooth Muscle

Smooth Muscle-Like Cells

Conclusion

Acknowledgments

REFERENCES

Chapter 89. Microcirculation

Introduction

Architecture of the Microcirculation

Arterioles and Arteriolar Smooth Muscle

Capillaries and Pericytes

Venules

Summary and Conclusions

Acknowledgments

REFERENCES

Chapter 90. Uterine Smooth Muscle

Excitation–Contraction Coupling in the Myometrium

Effects of Female Hormones on the Myometrium

Parturition

Conclusions

REFERENCES

Section C: Adaptations and Response

Chapter 91. Oxidative Stress, Endothelial Dysfunction, and Its Impact on Smooth Muscle Signaling

Introduction

The L-Arginine/No/cGMP Pathway in Vascular Tissue

Oxidative Stress and Endothelial Dysfunction

Endothelial Dysfunction and Cardiovascular Risk Factors

Vascular Superoxide Sources

Effects of Reactive Oxygen Species on the Activity and Expression of the sGC and the cGK-I

Oxidative Stress and Consequences for the Activity and Expression of the cGMP-Dependent Kinase I

Endothelial Function and Prognosis

Conclusion

REFERENCES

Chapter 92. Hemodynamic Control of Vascular Smooth Muscle Function

Introduction

Mechanical Forces in Vessel Physiology

Mechanosensitive Gene Expression Networks in VSMC

Mechanotransducers in VSMC

Recapitulation of Vascular Developmental Signaling

Conclusion

REFERENCES

Chapter 93. Myogenic Tone and Mechanotransduction

Myogenic Tone and Mechanotransduction

The Myogenic Response in Microcirculatory Control

The Underlying Mechanism(s)

Future Considerations

Acknowledgments

REFERENCES

Chapter 94. Cell–Cell Communication Through Gap Junctions

Coordination of Organ Function

Gap Junctions are Clusters of Intercellular Channels Formed by Connexins

Functional Aspects of Gap Junctional Coupling In Smooth Muscle In Specific Organs

Conclusion

REFERENCES

Chapter 95. Vascular Smooth Muscle Cell Phenotypic Adaptation

Normal Differentiated Phenotype of VSMC

Effectors of the Normal VSMC Differentiation Program

Conditions of VSMC Phenotypic Adaptation

Perspective

REFERENCES

Chapter 96. Molecular Pathways of Smooth Muscle Disease

Introduction

Migration

Proliferation

Inflammation

Conclusion

REFERENCES

Section D: Smooth Muscle Disease

Chapter 97. Genetic Variants in Smooth Muscle Contraction and Adhesion Genes Cause Thoracic Aortic Aneurysms and Dissections and Other Vascular Diseases

Introduction

Thoracic Aortic Aneurysms and Dissections

Mutations in Genes for SMC Contraction Proteins Cause Familial Thoracic Aortic Disease

Genetic Variants Contributing to Sporadic Thoracic Aortic Disease Disrupt Smooth Muscle Cell Contraction and Adhesion

ACTA2 Mutations Cause Occlusive Vascular Diseases in Addition to FTAAD

Syndrome of Global Smooth Muscle Dysfunction Due to a De Novo ACTA2 Mutation

Conclusion

REFERENCES

Chapter 98. Vascular Smooth Muscle Cell Remodeling in Atherosclerosis and Restenosis

Pathogenesis of Atherosclerosis and Vascular Remodeling

The Role of VSMC in Atheroma Evolution and Complications

Role of Adult Progenitor Cells in VSMC Remodeling During Atherosclerosis

Role of Genetics in VSMC Remodeling Leading to Atherosclerosis

Future Directions

REFERENCES

Chapter 99. Arterial Hypertension

Introduction

Vascular Smooth Muscle and Vascular Functional Changes in Hypertension

Vascular Smooth Muscle and Vascular Structural Changes in Hypertension

Molecular and Cellular Mechanisms of Vascular Remodeling

Vascular Smooth Muscle, Endothelial Function, and Hypertension-Associated Vascular Changes

Vascular Smooth Muscle, Inflammation, and Vascular Remodeling in Hypertension

Vascular Aging, Remodeling, and Hypertension

Vascular Calcification

Conclusions

Acknowledgments

REFERENCES

Chapter 100. Diabetic Vascular Disease

Introduction

Endothelial Dysfunction in Diabetes

The Role of Hyperglycemia in Endothelial Dysfunction

The Role of Hyperinsulinemia in Endothelial Dysfunction

The Role of the RAAS in Endothelial Dysfunction in Diabetes

The Role of Oxidative Stress in Diabetes-Related Endothelial Dysfunction

Conclusions

REFERENCES

Chapter 101. Vascular Mechanisms of Hypertension in the Pathophysiology of Preeclampsia

Preeclampsia

Placentation and the Origin of Preeclampsia

Placental Ischemia and Hypoxia

Endothelial Dysfunction in Preeclampsia

Potential Therapies for the Treatment of Preeclampsia

Conclusion

REFERENCES

Chapter 102. Erectile Dysfunction

Erectile Dysfunction is An Important Medical Condition

The Role of Smooth Muscle in Erectile Physiology

Maintenance of the Flaccid State

Initiation of An Erection

Biochemical Mechanisms Regulating Corporal Smooth Muscle Tone

The BK Channel Indirectly Blocks the L-Type Calcium Channel and is a Target For Treatment of Erectile Dysfunction

Calcium Sensitization of Smooth Muscle Cells

Regulation of Corporal Smooth Muscle Tone Through Changes in Myosin Isoform Expression

The Role of Androgens in Erectile Function

Mechanisms Underlying Priapism

Conclusion: Is it Easy to Treat Erectile Dysfunction?

REFERENCES

Chapter 103. Smooth Muscle in the Normal and Diseased Pulmonary Circulation

Introduction: Pulmonary Versus Systemic Circulations

Pulmonary Hypertension

Animal Models of Pulmonary Hypertension

Origins of Pulmonary Smc in Development and in Pulmonary Hypertensive Vascular Remodeling

Phenotypic and Functional Heterogeneity of PA-SMCs

Mechanisms Involved in Control of SMC (Or SM-Like Cell) Phenotype in Pulmonary Vascular Disease

Treatment of Pulmonary Hypertension

REFERENCES

Chapter 104. Airway Smooth Muscle and Asthma

Structure and Function of Airway Smooth Muscle

Excitation–Contraction Coupling and its Modulation in Asthma

Mechanical Adaptation of Airway Smooth Muscle

Molecular Mechanisms for Mechanical Adaptation of Airway Smooth Muscle

Regulation of Airway Smooth Muscle Function By Adhesion Complex Proteins

Summary and Conclusions

REFERENCES

Chapter 105. Aging

Introduction

Age-Related Modifications of Arterial Wall

Morphological and Functional Modifications of Aging SMCs

Modulation of Signaling Pathways in Aged SMC

Age-Related Accumulation of Advanced Glycosylation End Products in the Vessel Wall

Conclusions

REFERENCES

Chapter 106. Vascular Calcification

Clinical Significance

Clinical Interactions Between Vascular and Bone Therapies

REFERENCES

Chapter 107. Smooth Muscle Progenitor Cells: A Novel Target for the Treatment of Vascular Disease?

Introduction

The SPC Controversy

SPCs in Vascular Diseases

Molecular Mechanisms of Intimal SPC Accumulation

Therapeutic Options of Targeting SPCs

REFERENCES

Chapter 108. Smooth Muscle: Novel Targets and Therapeutic Approaches

Introduction

Novel Approaches to Therapeutic Targeting of Smooth Muscle Tissues

Summary and Conclusions

Acknowledgments

REFERENCES

Glossary

Index