The mechanisms underlying range of motion enhancements via flexibility training discussed in the literature show high heterogeneity in research methodology and study findings. In addition, scientific conclusions are mostly based on functional observations while studies considering the underlying physiology are less common. However, understanding the underlying mechanisms that contribute to an improved range of motion through stretching is crucial for conducting comparable studies with sound designs, optimising training routines and accurately interpreting resulting outcomes. While there seems to be no evidence to attribute acute range of motion increases as well as changes in muscle and tendon stiffness and pain perception specifically to stretching or foam rolling, the role of general warm-up effects is discussed in this paper. Additionally, the role of mechanical tension applied to greater muscle lengths for range of motion improvement will be discussed. Thus, it is suggested that physical training stressors can be seen as external stimuli that control gene expression via the targeted stimulation of transcription factors, leading to structural adaptations due to enhanced protein synthesis. Hence, the possible role of serial sarcomerogenesis in altering pain perception, reducing muscle stiffness and passive torque, or changes in the optimal joint angle for force development is considered as well as alternative interventions with a potential impact on anabolic pathways. As there are limited possibilities to directly measure serial sarcomere number, longitudinal muscle hypertrophy remains without direct evidence. The available literature does not demonstrate the necessity of only using specific flexibility training routines such as stretching to enhance acute or chronic range of motion.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that can lead to sudden cardiac death. Impact of genetic testing for the prognosis and treatment of patients with HCM needs to be improved. We conducted a systematic review and meta-analysis to investigate the characteristics and outcomes associated with sarcomere genotypes in index patients with HCM.
METHODS: A systematic search was conducted in Medline, Embase, and Cochrane Library up to Dec 31, 2023. Data on clinical characteristics, morphological and imaging features, outcomes and interventions were collected from published studies and pooled using a random-effects meta-analysis.
RESULTS: A total of 30 studies with 10,825 HCM index patients were included in the pooled analyses. The frequency of sarcomere genes in HCM patients was 41%. Sarcomere mutations were more frequent in women (p < 0.00001), and were associated with lower body mass index (26.1 ± 4.7 versus 27.5 ± 4.3; p = 0.003) and left ventricular ejection fraction (65.7% ± 10.1% vs. 67.1% ± 8.6%; p = 0.03), less apical hypertrophy (6.5% vs. 20.1%; p < 0.0001) and left ventricular outflow tract obstruction (29.1% vs. 33.2%; p = 0.03), greater left atrial volume index (43.6 ± 21.1 ml/m2 vs. 37.3 ± 13.0 ml/m2; p = 0.02). Higher risks of ventricular tachycardia (23.4% vs. 14.1%; p < 0.0001), syncope (18.3% vs. 10.9%; p = 0.01) and heart failure (17.3% vs. 14.6%; p = 0.002) were also associated with sarcomere mutations.
CONCLUSIONS: Sarcomere mutations are more frequent in women, and are associated with worse clinical characteristics and poor outcomes.

Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.

Understanding passive skeletal muscle mechanics is critical in defining structure-function relationships in skeletal muscle and ultimately understanding pathologically impaired muscle. In this systematic review, we performed an exhaustive literature search using PRISMA guidelines to quantify passive muscle mechanical properties, summarized the methods used to create these data, and make recommendations to standardize future studies. We screened over 7500 papers and found 80 papers that met the inclusion criteria. These papers reported passive muscle mechanics from single muscle fiber to whole muscle across 16 species and 54 distinct muscles. We found a wide range of methodological differences in sample selection, preparation, testing, and analysis. The systematic review revealed that passive muscle mechanics is species and scale dependent-specifically within mammals, the passive mechanics increases non-linearly with scale. However, a detailed understanding of passive mechanics is still unclear because the varied methodologies impede comparisons across studies, scales, species, and muscles. Therefore, we recommend the following: smaller scales may be maintained within storage solution prior to testing, when samples are tested statically use 2-3 min of relaxation time, stress normalization at the whole muscle level be to physiologic cross-sectional area, strain normalization be to sarcomere length when possible, and an exponential equation be used to fit the data. Additional studies using these recommendations will allow exploration of the multiscale relationship of passive force within and across species to provide the fundamental knowledge needed to improve our understanding of passive muscle mechanics.

Cardiac myosin binding protein-C (cMyBP-C) is a fundamental component of the cardiac sarcomere involved in regulating systolic and diastolic activity, processes which must be tightly maintained to preserve cardiac function. Importantly, as a non-enzymatic protein, cMyBP-C relies solely on post-translational modifications and protein-protein interactions in order to modulate its function, and does so through phosphorylation, glutathionylation and acetylation amongst others. Although some are better understood than others, these modifications may represent novel therapeutic routes to modulate cMyBP-C function in the treatment of cardiac disease.

TRPV2 is a well-conserved channel protein expressed in almost all tissues. Cardiomyocyte TRPV2 is expressed in the intercalated disks of the cardiac sarcomeres, where it is involved in maintaining the proper mechanoelectric coupling and structure. It is also abundantly expressed in the intracellular pools, mainly the endoplasmic reticulum. Under pathological conditions, TRPV2 is translocated to the sarcolemma, where it mediates an abnormal [Ca]2+ entry that may contribute to disease progression. In addition, an intracellularly diffused TRPV2 expression is present in resident cardiac macrophages. Upon infection or inflammation, TRPV2 is engaged in early phagosomes and is, therefore, potentially involved in protecting the cardiac tissue. Following acute myocardial infarction, a profound elevated expression of TRPV2 is observed on the cell membrane of the peri-infarct macrophages. The macrophage TRPV2 may harbor a detrimental effect in cardiac recovery by increasing unfavorable migration and phagocytosis processes in the injured heart. Most reports suggest that while cardiac TRPV2 activation may be beneficial under specific physiological conditions, both cardiac- and macrophage-related TRPV2 blocking can significantly ameliorate disease progression in various pathological states. To verify this possibility, the time frame of TRPV2 overexpression and its mediated signaling need to be fully characterized in both cardiomyocyte and cardiac macrophage populations.

Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (P<0.001) and MACE (P<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (P=0.001) or chromosomal anomalies (P<0.001). MYH7 was involved in 48% of the sarcomere gene mutations. MYH7 and ACTC1 mutations had lower risk for MACE than MYBPC3 and TTN (P=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; P=0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis MYBPC3, TTN, arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.

Although the O-GlcNAcylation process was discovered in 1984, its potential role in the physiology and physiopathology of skeletal muscle only emerged 20 years later. An increasing number of publications strongly support a key role of O-GlcNAcylation in the modulation of important cellular processes which are essential for skeletal muscle functions. Indeed, over a thousand of O-GlcNAcylated proteins have been identified within skeletal muscle since 2004, which belong to various classes of proteins, including sarcomeric proteins. In this review, we focused on these myofibrillar proteins, including contractile and structural proteins. Because of the modification of motor and regulatory proteins, the regulatory myosin light chain (MLC2) is related to several reports that support a key role of O-GlcNAcylation in the fine modulation of calcium activation parameters of skeletal muscle fibres, depending on muscle phenotype and muscle work. In addition, another key function of O-GlcNAcylation has recently emerged in the regulation of organization and reorganization of the sarcomere. Altogether, this data support a key role of O-GlcNAcylation in the homeostasis of sarcomeric cytoskeleton, known to be disturbed in many related muscle disorders.

Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.