Objective: To observe the association between clinical phenotypes of hypertrophic cardiomyopathy (HCM) patients and a rare calcium channel and regulatory gene variation (Ca²⁺ gene variation) and to compare clinical phenotypes of HCM patients with Ca²⁺ gene variation, a single sarcomere gene variation and without gene variation and to explore the influence of rare Ca²⁺ gene variation on the clinical phenotypes of HCM. Methods: Eight hundred forty-two non-related adult HCM patients diagnosed for the first time in Xijing Hospital from 2013 to 2019 were enrolled in this study. All patients underwent exon analyses of 96 hereditary cardiac disease-related genes. Patients with diabetes mellitus, coronary artery disease, post alcohol septal ablation or septal myectomy, and patients who carried sarcomere gene variation of uncertain significance or carried>1 sarcomere gene variation or carried>1 Ca²⁺ gene variation, with HCM pseudophenotype or carrier of ion channel gene variations other than Ca²⁺ based on the genetic test results were excluded. Patients were divided into gene negative group (no sarcomere or Ca²⁺ gene variants), sarcomere gene variation group (only 1 sarcomere gene variant) and Ca²⁺ gene variant group (only 1 Ca²⁺ gene variant). Baseline data, echocardiography and electrocardiogram data were collected for analysis. Results: A total of 346 patients were enrolled, including 170 patients without gene variation (gene negative group), 154 patients with a single sarcomere gene variation (sarcomere gene variation group) and 22 patients with a single rare Ca²⁺ gene variation (Ca²⁺ gene variation group). Compared with gene negative group, patients in Ca²⁺ gene variation group had higher blood pressure and higher percentage of family history of HCM and sudden cardiac death (P<0.05); echocardiographic results showed that patients in Ca²⁺ gene variation group had thicker ventricular septum ((23.5±5.8) mm vs. (22.3±5.7) mm, P<0.05); electrocardiographic results showed that patients in Ca²⁺ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (400.6±47.2) ms, P<0.05) and higher RV5+SV1 ((4.51±2.26) mv vs. (3.50±1.65) mv, P<0.05). Compared with sarcomere gene variation group, patients in Ca²⁺ gene variation group had later onset age and higher blood pressure (P<0.05); echocardiographic results showed that there was no significant difference in ventricular septal thickness between two groups; patients in Ca²⁺ gene variation group had lower percentage of left ventricular outflow tract pressure gradient>30 mmHg (1 mmHg=0.133 kPa, 22.8% vs. 48.1%, P<0.05) and the lower early diastolic peak velocity of the mitral valve inflow/early diastolic peak velocity of the mitral valve annulus (E/e') ratio ((13.0±2.5) vs. (15.9±4.2), P<0.05); patients in Ca²⁺ gene variation group had prolonged QT interval ((416.6±23.1) ms vs. (399.0±43.0) ms, P<0.05) and lower percentage of ST segment depression (9.1% vs. 40.3%, P<0.05). Conclusion: Compared with gene negative group, the clinical phenotype of HCM is more severe in patients with rare Ca²⁺ gene variation; compared with patients with sarcomere gene variation, the clinical phenotype of HCM is milder in patients with rare Ca²⁺ gene variation.
Humans ; Cardiac Surgical Procedures/methods* ; Cardiomyopathy, Hypertrophic/genetics* ; Echocardiography ; Electrocardiography ; Phenotype ; Sarcomeres/genetics* ; Adult

Titin, the largest known protein in the body expressed in three isoforms (N2A, N2BA and N2B), is essential for muscle structure, force generation, conduction and regulation. Since the 1950s, muscle contraction mechanisms have been explained by the sliding filament theory involving thin and thick muscle filaments, while the contribution of cytoskeleton in force generation and conduction was ignored. With the discovery of insoluble protein residues and large molecular weight proteins in muscle fibers, the third myofilament, titin, has been identified and attracted a lot of interests. The development of single molecule mechanics and gene sequencing technology further contributed to the extensive studies on the arrangement, structure, elastic properties and components of titin in sarcomere. Therefore, this paper reviews the structure, isforms classification, elastic function and regulatory factors of titin, to provide better understanding of titin.
Connectin/genetics* ; Muscle Proteins/metabolism* ; Protein Isoforms/genetics* ; Sarcomeres/metabolism* ; Muscle Fibers, Skeletal/metabolism*

Objective: To analyze the clinical and genetic characteristics of clinical subtypes of non-obstructive hypertrophic cardiomyopathy (HCM). Methods: It was a cohort study. Patients with non-obstructive HCM admitted to Fuwai Hospital, Chinese Academy of Medical Sciences, from January 1999 to April 2019 were enrolled. According to the characteristics of cardiac morphology and function shown by echocardiography, the patients were divided into common type, dilated type, restricted type and reduced ejection fraction type. The clinical data of the patients were recorded, and 8 sarcomere pathogenic genes were screened by full exon sequencing or panel sequencing. Patienst were followed up and cardiovascular endpoint events were recorded. Results: A total of 815 patients with non-obstructive HCM were enrolled, including 27 (3.3%) restricted type, 51 (6.3%) dilated type, 30 (3.7%) reduced ejection fraction type and 707 (86.7%) common type. A total of 704 out of 815 patients underwent genetic testing. Among them, 299 (42.5%) patients carried at least 1 sarcomere gene mutation. MYBPC3 and MYH7 mutation accounted for 42.1% (126/299) and 35.8% (107/299) respectively. 66.7% (16/24) of the patients with restricted type carried sarcomere gene mutation, which was higher than that in patients with dilated type (36.4% (16/44)) and in common type (41.5% (250/602), P=0.015). Among the patients with reduced ejection fraction, 56.7% (17/30) patients carried sarcomere gene mutations, 23.3% (7/30) carried multiple sarcomere mutations, which was higher than that in restricted type (8.3% (2/24)), in dilated type (9.1% (4/44)) and in common type 4.2% ((24/577), P<0.001). MYH7 and MYBPC3 were the main mutation gene types of all clinical subtypes, and the genotypes were similar among groups (all P>0.05). Seven hundred and three out 815 patients were followed up for 2.9 (1.4, 4.0) years. There were 53(7.5%) cardiovascular death. Cardiovascular death occurred in 5.0% (29/578) patients with common type, 13.0% (3/23) patients with restricted type, 16.3% (7/43) patients with dilated type and 46.7% (14/30) patients with decreased ejection fraction. Univariate Cox proportional hazards model analysis showed that the risk of cardiovascular death in patients with restricted, dilated and reduced ejection fraction type was higher than that in patients with common type (P<0.001). After adjusting for gender, age of onset, body mass index, history of hypertension, coronary heart disease and diabetes, multivariate Cox proportional hazards model analysis showed that the HR of cardiovascular death in patients with restricted, dilated and reduced ejection fraction type were 5.454 (95%CI 1.137-26.157, P=0.034) and 6.597 (95%CI 1.632-26.667, P=0.008) and 9.028 (95%CI 2.201-37.039, P=0.002) respectively, as compared to patients with common type. Conclusions: Most of the patients with non-obstructive HCM are common type, featured by mild clinical manifestations and good prognosis. Although the proportion of restricted type and dilated type is relatively low, and cardiac systolic function is mostly preserved, the clinical phenotype and prognosis of these patients are similarly severe and poor as patients with reduced ejection fraction. The genotypes are similar in different clinical subtypes, but the proportion of patients with sarcomere gene mutation is higher in restricted type, and the proportion of patients with multiple sarcomere gene mutation is higher in decreased ejection fraction type.
Cardiomyopathy, Hypertrophic/genetics* ; Cohort Studies ; Humans ; Mutation ; Phenotype ; Sarcomeres/genetics*

This study aimed to investigate the effects of acupuncture intervention on excessive eccentric training-induced changes of perimysial junctional plates (PJPs) domain. Thirty healthy male Wistar rats were randomly assigned to 5 groups: control group, four-week training group, four-week training + 1-week recovery group and four-week training + 1-week acupuncture group. Rats were subjected to continuous excessive eccentric training for 4 weeks (incline -16°, speed 16-20 m/min, 60-90 min/d, 5 day per week), and then were subjected to one-week spontaneous recovery or one-week recovery with acupuncture intervention (a piece of filiform needle for 4 min every day). The PJPs domain changes were observed under transmission electron microscopy, and the perimysial collagen network structural changes were examined by scanning electron microscopy with or without a digestion technique (NaOH). The following results were obtained: (1) Compared with control group, PJPs domain of four-week training group showed excessive shortening of sarcomere (P < 0.001), serious damage of sarcomere structure, and altered mitochondria morphology in intermyofibria and subsarcolemma; 54% degradation of sarcolemma, and increased number of caveolae (P < 0.01); reduced number of PJPs (P < 0.001). (2) In comparison with four-week training group, PJPs domain was slightly changed in four-week training + 1-week recovery group, i.e., partial recovery of sarcomere length and structure (accounting for 85.23% of control group), and recovery of intermyofibrial and subsarcolemmal mitochondria morphology; decreased sarcolemmal degradation (P < 0.001), and increased number of caveolae (P < 0.05); increased PJPs number (P < 0.001). (3) PJPs domain changed in four-week training + 1-week acupuncture group compared with four-week training + 1-week recovery group, which were substantial recovery of sarcomere length (accounting for 94.51% of control group), increased subsarcolemmal mitochondrial fusion (P < 0.001), decreased caveolae number (P < 0.001), and decreased PJPs number (P < 0.001). The results indicated that excessive eccentric training resulted in excessively reduced number of PJPs with altered PJPs domain homeostasis, thus impeding the adaptability to eccentric training. After 1 week of natural recovery, the number of PJPs was excessively increased, hindering muscle damage repair. Acupuncture intervention helped to recover PJPs number and PJPs domain homeostasis, thus significantly relieving overuse injuries.
Acupuncture Therapy ; Animals ; Male ; Microscopy, Electron, Transmission ; Mitochondria ; ultrastructure ; Muscle, Skeletal ; ultrastructure ; Physical Conditioning, Animal ; Random Allocation ; Rats ; Rats, Wistar ; Sarcomeres ; ultrastructure

The fact that different types of cardiomyopathies can be manifested by the same sarcomere protein gene mutation in a single family is well known. However, mixed features of different types of cardiomyopathies in a single patient have not been well appreciated. We identified a novel mutation in cardiac troponin I3 (Arg186Gly) in the present case, and two of the family members showed mixed morphologic features of hypertrophic cardiomyopathy and left ventricular non-compaction. Moreover, both the features of cardiomyopathies were not apparent for each type of cardiomyopathy. In the patient's family, four other members had unexpected deaths before the age of 30.
Cardiomyopathies* ; Cardiomyopathy, Hypertrophic ; Cardiomyopathy, Restrictive ; Humans ; Sarcomeres ; Troponin*

Genetic diagnosis of cardiomyopathies is challenging, due to the marked genetic and allelic heterogeneity and the lack of knowledge of the mutations that lead to clinical phenotypes. Here, we present the case of a large family, in which a single TNNI3 mutation caused variable phenotypic expression, ranging from restrictive cardiomyopathy (RCMP) to hypertrophic cardiomyopathy (HCMP) to near-normal phenotype. The proband was a 57-year-old female with HCMP. Examining the family history revealed that her elder sister had expired due to severe RCMP. Using a next-generation sequencing-based gene panel to analyze the proband, we identified a known TNNI3 gene mutation, c.433C>T, which is predicted to cause an amino acid substitution (p.Arg145Trp) in the highly conserved inhibitory region of the cardiac troponin I protein. Sanger sequencing confirmed that six relatives with RCMP or near-normal phenotypes also carried this mutation. To our knowledge, this is the first genetically confirmed family with diverse phenotypic expression of cardiomyopathies in Korea. Our findings demonstrate familial implications, where a single mutation in a sarcomere protein can cause diverse phenotypic expression of cardiomyopathies.
Amino Acid Substitution ; Cardiomyopathies* ; Cardiomyopathy, Hypertrophic ; Cardiomyopathy, Restrictive ; Diagnosis ; Female ; Humans ; Korea ; Middle Aged ; Phenotype ; Population Characteristics ; Sarcomeres ; Siblings ; Troponin I

Cardiotrophin-1 (CT-1) activates a distinct form of cardiac muscle cell hypertrophy in which the sarcomeric units are assembled in series. The aim of the study was to determine the expression pattern of sarcomeric contractile protein α-actin, specialized cytoskeletal protein α-actinin and mitochondrial uncoupling protein-2 (UCP2) in myocardial remodeling induced by chronic exposure to CT-1. Kunming mice were intraperitoneally injected with carboxy-terminal polypeptide (CP) of CT-1 (CT-1-CP, 500 μg·kg(-1)· day(-1)) for 1, 2, 3 and 4 week (s), respectively (4 groups obtained according to the injection time, n=10 each, with 5 males and 5 females in each group). Those injected with physiological saline for 4 weeks served as controls (n=10, with 5 males and 5 females). The heart tissues of mice were harvested at 1, 2, 3 or 4 week (s). Immunohistochemistry (IHC) and Western blotting (WB) were used to detect the distribution and expression of sarcomeric α-actin, α-actinin and mitochondrial UCP2 in myocardial tissues. IHC showed that α-actin was mainly distributed around the nuclei of cardiomyocytes, α-actinin concentrated around the striae and UCP2 scattered rather evenly in the plasma. The expression of α-actin was slightly greater than that of α-actinin and UCP2 in the control group (IHC: χ(2)=6.125; WB: F=0.249, P>0.05) and it gradually decreased after exposure to CT-1-CP. There was no significant difference in the expression of α-actin between the control group and the CT-1-CP-treated groups (χ (2)=7.386, P>0.05). But Western blotting revealed significant difference in the expression of α-actin between the control group and the 4-week CT-1-CP-treated group (F=2.912; q=4.203, P<0.05). Moreover, it was found that the expression of α-actinin increased stepwise with the exposure time in CT-1-CP-treated groups and differed significantly between CT-1-CP-treated groups and the control group (ICH: χ (2)=21.977; WB: F=50.388; P<0.01). The expression of UCP2 was initially increased (WB: control group vs. 1- or 2-week group, q values: 5.603 and 9.995, respectively, P<0.01) and then decreased (WB: control group vs. 3-week group, q=4.742, P<0.01; control group vs. 4-week group, q=0.558, P>0.05). It was suggested that long-term exposure to CT-1-CP could lead to the alteration in the expression of sarcomeric α-actin, α-actinin and mitochondrial UCP2. The different expressions of sarcomeric structure proteins and mitochondrial UCP2 may be involved in myocardial remodeling.
Actinin ; biosynthesis ; Actins ; biosynthesis ; Animals ; Cardiomegaly ; chemically induced ; metabolism ; pathology ; Cytokines ; adverse effects ; pharmacology ; Female ; Gene Expression Regulation ; drug effects ; Ion Channels ; biosynthesis ; Male ; Mice ; Mitochondrial Proteins ; biosynthesis ; Myocardium ; metabolism ; pathology ; Sarcomeres ; metabolism ; pathology ; Uncoupling Protein 2

BACKGROUND/AIMS: External anal sphincter (EAS) and puborectalis muscle (PRM) play important role in anal continence function. Based on length-tension measurement, we recently reported that the human EAS muscle operates at short sarcomere length under physiological conditions. Goal of our study was to determine if PRM also operates at the short sarcomere length. METHODS: Length-tension relationship of the PRM muscle was studied in vivo in 10 healthy nullipara women. Length was altered by vaginal distension using custom-designed probes of 5, 10, 15, 20, 25 and 30 mm diameters as well as by distending a polyethylene bag with different volumes of water. Probes were equipped with a reverse perfuse sleeve sensor to measure vaginal pressure (surrogate of PRM tension). PRM electromyogram (EMG) was recorded using wire electrodes. Three-dimensional ultra-sound images were obtained to determine effect of vaginal distension on PRM length. RESULTS: Ultrasound images demonstrate distension volume dependent increase in PRM length. Rest and squeeze pressures of vaginal bag increased with the increase in bag volume. Similarly, the change in vaginal pressure, which represents the PRM contraction increased with the increase in the probe size. Increase in probe size was not associated with an increase in EMG activity (a marker of neural drive) of the PRM. CONCLUSIONS: Probe size dependent increase in PRM contraction pressure, in the presence of constant EMG (neural input) proves that the human PRM operates at short sarcomere length. Surgically adjusting the PRM length may represent a novel strategy to improve treat anal continence and possibly other pelvic floor disorders.
Anal Canal ; Electrodes ; Fecal Incontinence* ; Female ; Humans ; Muscles ; Pelvic Floor Disorders* ; Polyethylene ; Sarcomeres ; Ultrasonography ; Water

Muscle pain is one of the most common, as well as elusive, clinical complaints. Pain can be experienced in muscles by any dysfunction of the muscle itself, peripheral nerves, or central nervous system. Persistent inflammation of the muscle increases nerve endings of the nociceptors and can develop allodynia or hyperalgesia. Myofascial trigger points are formed by perpetuating contraction of the sarcomeres and local ischemia and can result in regional pain. Disorders of the peripheral nervous system can entail muscle pain in the innervated territory. The central nervous system can also modulate or generate muscle pain. Gate-control theory provides an explanation as to how pain can be affected by the nervous system. Fibromyalgia is believed to be related to a lowered pain threshold in the central nervous system. Clinicians, during their diagnostic approach, should not unduly attribute muscle pain to pathology confined to the muscle merely because pain is perceived and evoked from the muscle. Even in cases where abnormalities are confirmed in the muscle, such as myofascial trigger points, clinicians should seek the underlying etiology. In particular, diagnosis of myofascial pain syndrome does not rule out primary musculoskeletal disorders. Rather, arthropathies or radiculopathies are known to frequently involve myofascial pain syndrome, which would not improve unless they are resolved. After accurate diagnosis of muscle pain is obtained, appropriate treatment should be implemented. A multi-disciplinary, individualized approach, including physiotherapy, exercise, education, and behavioral modification, is recommended.
Central Nervous System ; Contracts ; Fibromyalgia ; Hyperalgesia ; Inflammation ; Ischemia ; Muscles ; Myofascial Pain Syndromes ; Nerve Endings ; Nervous System ; Nociceptors ; Pain Threshold ; Peripheral Nerves ; Peripheral Nervous System ; Radiculopathy ; Sarcomeres ; Trigger Points

Muscle wasting is commonly seen in patients with sepsis as a consequence of the catabolic response in skeletal muscle. Muscle wasting can occur in cases that have an imbalance between degradation and synthesis of muscle proteins. Although decrements in the synthesis of muscle proteins may contribute to sepsis-induced muscle wasting, it has been recognized that increments in its degradation play a more essential role in muscle wasting. Muscle wasting in sepsis patients has some significant clinical consequences such as reduced ambulation and exercise tolerance, and an increased risk for pulmonary and thromboembolic complications. Several mechanisms have been proposed for sepsis-induced muscle wasting. Increased proteolysis via the ubiquitin-proteasome pathway and the calpains system is one of the principal mechanisms of muscle wasting induced by sepsis. Calpains are activated by calcium, which increases in patients with sepsis. The activation of the calpains system disrupts the sarcomere of the myofibrils, resulting in the release of myofilaments that are subsequently ubiquitinated and degraded by the 26S proteasome complex. Recent studies have suggested that transcriptional factors such as NF-kappaB and FoxO, and the apoptosis and autophagy-lysosome pathways may also be involved in sepsis-induced muscle wasting. This review briefly summarizes the contribution of these mechanisms of muscle wasting in patients with sepsis and the possible therapeutic agents to treat it.
Apoptosis ; Atrophy ; Calcium ; Calpain ; Exercise Tolerance ; Humans ; Muscle Proteins ; Muscle, Skeletal ; Muscles ; Myofibrils ; NF-kappa B ; Proteasome Endopeptidase Complex ; Proteolysis ; Sarcomeres ; Sepsis ; Ubiquitin ; Walking