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Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are \"private\" or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.

The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (Actn2) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation. Actn2 mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition, Actn2 mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in Actn2 mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation. Actn2 mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in Actn2 and Srf mutant cardiomyocytes. Together, these data indicate that Actn2-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.

A muscle’s structure, or architecture, is indicative of its function and is plastic; changes in input to or use of the muscle alter its architecture. Stroke-induced neural deficits substantially alter both input to and usage of individual muscles. We combined in vivo imaging methods (second-harmonic generation microendoscopy, extended field-of-view ultrasound, and fat-suppression MRI) to quantify functionally meaningful architecture parameters in the biceps brachii of both limbs of individuals with chronic hemiparetic stroke and in age-matched, unimpaired controls. Specifically, serial sarcomere number (SSN) and physiological cross-sectional area (PCSA) were calculated from data collected at three anatomical scales: sarcomere length, fascicle length, and muscle volume. The interlimb differences in SSN and PCSA were significantly larger for stroke participants than for participants without stroke (P = 0.0126 and P = 0.0042, respectively), suggesting we observed muscle adaptations associated with stroke rather than natural interlimb variability. The paretic biceps brachii had ∼8,200 fewer serial sarcomeres and ∼2 cm² smaller PCSA on average than the contralateral limb (both P < 0.0001). This was manifested by substantially smaller muscle volumes (112 versus 163 cm³), significantly shorter fascicles (11.0 versus 14.0 cm; P < 0.0001), and comparable sarcomere lengths (3.55 versus 3.59 μm; P = 0.6151) between limbs. Most notably, this study provides direct evidence of the loss of serial sarcomeres in human muscle observed in a population with neural impairments that lead to disuse and chronically place the affected muscle at a shortened position. This adaptation is consistent with functional consequences (increased passive resistance to elbow extension) that would amplify already problematic, neurally driven motor impairments.

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4 . In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect. Here, Michael Gollob and colleagues perform a whole exome sequencing study to identify a mutation in the atrial-specific myosin light chain gene MYL4 in a small family with autosomal dominant familial atrial fibrillation. They also test the functionality of this MYL4 mutation in zebrafish cardiac function and recapitulate disease-related phenotypes.

This study analyzed the changes in the composition of thin filaments in spastic muscles after stroke to investigate the mechanism underlying changes in the sarcomeres. Twenty-four rats were randomly divided into four groups: normal, and 3, 6, and 9 days after stroke. A model of post-stroke gastrocnemius muscle spasm was created. Quantitative proteomic procedure and bioinformatics analysis revealed significant changes in cytoskeletal protein expressions in gastrocnemius muscles of each stroke group, particularly those on thin filaments. On the 3rd day after stroke, proteins upregulated within the thin filaments included actin-binding LIM protein 1, tropomyosin 3, leiomodin 2, drebrin-like protein, parvin beta, capping actin protein-gelsolin like, actinin alpha 2, and PDZ-LIM-domain protein 1, while downregulated proteins included tropomyosin 1, gelsolin, actinin alpha 3, and PDZ-LIM-domain protein 7. On the sixth day, upregulation of tropomyosin 2 was newly added while parvin alpha, destrin, PDZ-LIM-domain protein 3, leiomodin 3 were downregulated. On the 9th day, actinin alpha 2, PDZ-LIM-domain protein 7, and cofilin 2 were downregulated. These altered proteins are capable of promoting actin filament elongation and regulating Z-disc growth, and changes in their expression may be responsible for the changes in spastic muscle sarcomere after stroke.

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current literature clearly shows that hPSC-CMs recapitulate many molecular, cellular, and functional aspects of human heart pathophysiology and their responses to cardioactive drugs. Here, we provide a comprehensive overview of hPSC-CMs models that have been described to date and highlight their most recent and remarkable contributions to research on cardiovascular diseases and disorders with cardiac traits. We conclude discussing immediate challenges, limitations, and emerging solutions.

Pathological obesity can result from genetic predisposition, obesogenic diet, and circadian rhythm disruption. Obesity compromises function of muscle, which accounts for a majority of body mass. Behavioral intervention that can counteract obesity arising from genetic, diet or circadian disruption and can improve muscle function holds untapped potential to combat the obesity epidemic. Here we show that Drosophila melanogaster (fruit fly) subject to obesogenic challenges exhibits metabolic disease phenotypes in skeletal muscle; sarcomere disorganization, mitochondrial deformation, upregulation of Phospho-AKT level, aberrant intramuscular lipid infiltration, and insulin resistance. Imposing time-restricted feeding (TRF) paradigm in which flies were fed for 12 h during the day counteracts obesity-induced dysmetabolism and improves muscle performance by suppressing intramuscular fat deposits, Phospho-AKT level, mitochondrial aberrations, and markers of insulin resistance. Importantly, TRF was effective even in an irregular lighting schedule mimicking shiftwork. Hence, TRF is an effective dietary intervention for combating metabolic dysfunction arising from multiple causes. Time-restricted feeding (TRF) has beneficial metabolic effects. Here the authors examine how TRF impacts muscle physiology using fly models of metabolically adverse conditions, including diet and genetic models of obesity as well as circadian rhythm disruption, and find that TRF ameliorates skeletal muscle dysfunction.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebra-fish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c +/− fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c −/− larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.

Mechanical stress from cardiomyocyte contraction causes misfolded sarcomeric protein replacement. Sarcomeric maintenance utilizes localized pools of mRNAs and translation machinery, yet the importance of localized translation remains unclear. In this issue of the JCI, Haddad et al. identify the Z-line as a critical site for localized translation of sarcomeric proteins, mediated by ribosomal protein SA (RPSA). RPSA localized ribosomes at Z-lines and was trafficked via microtubules. Cardiomyocyte-specific loss of RPSA in mice resulted in mislocalized protein translation and caused structural dilation from myocyte atrophy. These findings demonstrate the necessity of RPSA-dependent spatially localized translation for sarcomere maintenance and cardiac structure and function.

Nebulin is a giant protein that winds around the actin filaments in the skeletal muscle sarcomere. Compound-heterozygous mutations in the nebulin gene ( NEB ) cause typical nemaline myopathy (NM), a muscle disorder characterized by muscle weakness with limited treatment options. We created a mouse model with a missense mutation p.Ser6366Ile and a deletion of NEB exon 55, the Compound-Het model that resembles typical NM. We show that Compound-Het mice are growth-retarded and have muscle weakness. Muscles have a reduced myofibrillar fractional-area and sarcomeres are disorganized, contain rod bodies, and have longer thin filaments. In contrast to nebulin-based severe NM where haplo-insufficiency is the disease driver, Compound-Het mice express normal amounts of nebulin. X-ray diffraction revealed that the actin filament is twisted with a larger radius, that tropomyosin and troponin behavior is altered, and that the myofilament spacing is increased. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets. Nebulin-based nemaline myopathy is a heterogenous disease with unclear pathological mechanisms. Here, the authors generate a mouse model that mimics the most common genetic cause of the disease and demonstrate that muscle weakness in this model is associated with twisted actin filaments and altered tropomyosin and troponin behaviour.