ABSTRACT
Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (<5% of control), contain nemaline rods and undergo fiber-type switching toward oxidative types. Nebulin deficiency causes a large deficit in specific force, and mechanistic studies provide evidence that a reduced fraction of force-generating cross-bridges and shortened thin filaments contribute to the force deficit. Muscles rich in glycolytic fibers upregulate proteolysis pathways (MuRF-1, Fbxo30/MUSA1, Gadd45a) and undergo hypotrophy with smaller cross-sectional areas (CSAs), worsening their force deficit. Muscles rich in oxidative fibers do not have smaller weights and can even have hypertrophy, offsetting their specific-force deficit. These studies reveal nebulin as critically important for force development and trophicity in adult muscle. The Neb cKO phenocopies important aspects of NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness.
Subject(s)
Muscle Proteins/deficiency , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Myopathies, Nemaline/genetics , Myopathies, Nemaline/pathology , Sarcomeres/metabolism , Animals , Disease Models, Animal , Gene Expression , Gene Expression Profiling , Mice , Mice, Knockout , Muscle Contraction/genetics , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Muscle Fibers, Skeletal/ultrastructure , Muscle Proteins/genetics , Muscle Weakness/genetics , Muscle Weakness/pathology , Muscle, Skeletal/physiopathology , Muscle, Skeletal/ultrastructure , Myopathies, Nemaline/mortality , Myosins/genetics , Myosins/metabolism , Phenotype , Sarcomeres/pathologySubject(s)
Arthrogryposis , Fetal Diseases , Fetal Movement , Hypokinesia , Myopathies, Nemaline , Abnormalities, Multiple , Arthrogryposis/epidemiology , Arthrogryposis/physiopathology , Female , Fetus/pathology , Fetus/physiopathology , Humans , Hypokinesia/physiopathology , Infant, Newborn , Muscular Diseases/genetics , Myopathies, Nemaline/epidemiology , Myopathies, Nemaline/mortality , Myopathies, Nemaline/physiopathology , PregnancyABSTRACT
A case is presented of a female newborn infant delivered with an Apgar Score of 1, who could not be resuscitated. There was a high arched palate, bell-shaped chest, contractures of writes inflexion, ankles and knees in extension, and intrauterine fractures. Clinical discussion led to a diagnosis of arthrogryposis secondary to fetal akinesia syndrome caused by nemaline myopathy. Pathology and pathologic discussion confirmed this diagnosis.
Subject(s)
Arthrogryposis/diagnosis , Hypokinesia/diagnosis , Myopathies, Nemaline/diagnosis , Abnormalities, Multiple/diagnosis , Adult , Arthrogryposis/mortality , Arthrogryposis/pathology , Craniofacial Abnormalities/diagnosis , Female , Fetal Diseases/diagnosis , Humans , Hypokinesia/complications , Infant, Newborn , Lung/abnormalities , Movement Disorders , Myopathies, Nemaline/mortality , Myopathies, Nemaline/pathology , Pregnancy , Thorax/abnormalitiesABSTRACT
We report 143 Australian and North American cases of primary nemaline myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty-two patients had skeletal muscle actin mutations and 4 had mutations in the alpha-tropomyosin(slow) gene. Obstetric complications occurred in 49 cases. Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy.
Subject(s)
Myopathies, Nemaline/physiopathology , Respiratory Insufficiency/physiopathology , Adult , Child , Humans , Infant , Middle Aged , Mutation/genetics , Myopathies, Nemaline/genetics , Myopathies, Nemaline/mortality , Phenotype , Prognosis , Respiratory Insufficiency/genetics , Respiratory Insufficiency/mortality , Survival AnalysisABSTRACT
Two children are reported who are notable exceptions to the rule of early mortality reported for neonates with severe nemaline rod myopathy. Their conditions improved progressively from birth with full pediatric critical care unit support. They achieved respiratory independence at 22 months and 15 months and now at ages 29 months and 17 months, respectively, they are cognitively normal and demonstrating progressive improvement in muscle strength.
