Cardiac sarcomere mechanics in health and disease

The sarcomere is the fundamental structural and functional unit of striated muscle and is directly responsible for most of its mechanical properties. The sarcomere generates active or contractile forces and determines the passive or elastic properties of striated muscle. In the heart, mutations in sarcomeric proteins are responsible for the majority of genetically inherited cardiomyopathies. Here, we review the major determinants of cardiac sarcomere mechanics including the key structural components that contribute to active and passive tension. We dissect the molecular and structural basis of active force generation, including sarcomere composition, structure, activation, and relaxation. We then explore the giant sarcomere-resident protein titin, the major contributor to cardiac passive tension. We discuss sarcomere dynamics exemplified by the regulation of titin-based stiffness and the titin life cycle. Finally, we provide an overview of therapeutic strategies that target the sarcomere to improve cardiac contraction and filling.

Impact of chronic obstructive pulmonary disease on passive viscoelastic components of the musculoarticular system

Chronic obstructive pulmonary disease (COPD) produces skeletal muscle atrophy and weakness, leading to impairments of exercise performance. The mechanical work needed for movement execution is also provided by the passive tension developed by musculoarticular connective tissue. To verify whether COPD affects this component, the passive viscoelastic properties of the knee joint were evaluated in 11 patients with COPD and in 11 healthy individuals. The levels of stiffness and viscosity were assessed by means of the pendulum test, consisting in a series of passive leg oscillations. In addition, to explore the contribution of passive tension in the mechanical output of a simple motor task, voluntary leg flexion–extension movements were performed. Patients with COPD showed a statistically significant reduction in stiffness and viscosity compared to controls. Voluntary execution of flexion–extension movements revealed that the electromyographic activity of the Rectus Femoris and Biceps Femoris was lower in patients than in controls, and the low viscoelastic tension in the patients conditioned the performance of active movements. These results provide novel insights on the mechanism responsible for the movement impairments associated with COPD.

The static preload associated myogenic spontaneous fasciculation response in lengthening cardiac muscle

The passive tension force enhancement is one kind of myogenic spontaneous fasciculation in muscles. However, its physiological properties in cardiac fibres are not well known. In this study, mice cardiac papillary muscle spontaneous force enhancement was evaluated by micro stepping stretch method. The occurrence of spontaneous force and real time cardiac fibre Ca2+ redistribution was tranced by Flou-3 (2mM) indicator. Force enhancement amplitude, enhancement prolonging time, and tension–time integral were analysis by myograph analyser. The results indicated that the spontaneous force occurred immediately after the active stretch, rapidly enhanced during tolerating the sustained static stretch. The force occurrence and amplitude enhance synchronized with the Ca2+ recruitment and lightning transmitted to adjacent fibres. In high preload fibres, the enhancement was forceful to over its maximum passive tension (6.20 ± 0.51 N/mm2 to 4.49 ± 0.43 N/mm2). The force occurrences were unsteadiness in each stretch. The increased enhancement amplitude combining with the shortening prolonging time induced reduction of tension–time integral. We concluded that the intracellular Ca2+ synchronized force enhancement is one kind of interruption event in overloading cardiac fibres. This interruption occurred during the relaxation processing in cardiac muscle, therefore affect the rhythmic stability of cardiac relaxation-contraction cycle.

Age-related reductions in the number of serial sarcomeres contribute to shorter fascicle lengths but not elevated passive tension

We investigated age-related changes to fascicle length (FL), sarcomere length (SL), and serial sarcomere number (SSN), and how this affects passive force. Following mechanical testing to determine passive force, the medial gastrocnemius muscle of young (n=9) and old (n=8) Fisher 344BN hybrid rats was chemically fixed at the optimal muscle length for force production; individual fascicles were dissected for length measurement, and laser diffraction was used to assess SL. Old rats had ∼14% shorter FL than young, which was driven by a ∼10% reduction in SSN, with no difference in SL (∼4%). Passive force was greater in the old compared to young rats at long muscle lengths. Shorter FL and reduced SSN in the old rats could not entirely explain increased passive forces for absolute length changes, owing to a slight reduction in SL in old, resulting in similar SL at long muscle lengths.Summary StatementThis study sought to explain the increased passive tension observed for muscles of older individuals owing to age-related changes to muscle architecture.

Dextran sulfate sodium salt corrupted colonic crypts declined the smooth muscle tension in mouse large intestine

Ulcerative colitis is one kind of colonic mucosa damage, shows high number of inflammatory epithelial cells. Dextran sulfate sodium salt (DSS) induce a milder onset of colitis or a more aggressive response. It may damage the protective effects on intestinal barrier. In this study, we investigated the damaging of colon crypts, evaluated the smooth muscle tension beneath corrupted crypts in DSS exposed mice.Methodsfemale specific-pathogen-free BALB/C mice (n=16) are randomly divided as: group A: control mice (n=4); group B: DSS-mice (colitis, 5% DSS in drink water, days 1 to 7, n = 12). The DSS is replaced every 2 days. On day 8, mice colons are excised from the colon-cecal junction to the anus. The distal colon segment is longitude incision and aberrant crypt area are determined by methylene blue staining method. The smooth muscle strip is separated and prepared for passive tension tests. The rest segment is fixed with 10% formalin and embedded in paraffin. Histological scores are evaluated in hematoxylin-eosin staining section: crypt damage (none = 0, basal 1/3 damaged = 1, basal 2/3 damaged = 2, only the surface epithelium is intact = 3, and entire crypt and epithelium are lost = 4). The smooth muscle passive tension beneath the aberrant crypt area in DSS-mice are tested and compared with the preparations from control mice.ResultsIn DSS uptake mice, the inflammation in large intestine mucosa damaged crypts with architectural distortions on day 7 (n=7). In crypts damage area, the smooth muscle passive tension and relative myogenic spontaneous contraction parameters are significantly reduced under the high preload conditions. The maximum rate of change of velocity of spontaneous contraction was noticeable attenuated.ConclusionOur findings demonstrate that low dosage DSS water drink result in corrupted colonic crypts. The corrupted crypts damage the large intestinal epithelium barrier, affect the smooth muscle functions, which declined in myogenic spontaneous contraction under the preload. This further may reduce the peristalsis in large intestine.

Abstract MP105: Python Post-prandial Cardiac Adaptation is Supported by Enhanced Metabolism, Reduced Sarcomere Passive Tension, and Epigenetic Remodeling

Pythons are infrequent feeders that can ingest meals equal to their own body mass. The extreme metabolic response required to digest such large meals is associated with a dramatic increase in the mass of most organs, including the heart. Recently, we have been able to assess functional effects of feeding using isolated python cardiomyocytes and myofibrils, advancing our understanding of extreme cardiac adaptation in python ( Python regius ). Twenty-four hours after feeding, python cardiomyocytes showed prolonged Ca 2+ transients, increased maximal tension and Ca 2+ sensitivity of myofibrils as compared to fasted pythons. Post-prandial positive inotropy was accompanied by enhanced metabolic output via increased mitochondrial ATP production rate and by AMP-dependent kinase (AMPK) activation and phosphofructokinase-2 reduction, suggesting a key role for fatty acid, but not glucose, metabolism after feeding. In addition, 24h post-fed hearts had significantly reduced tissue stiffness and myofibril passive tension. Finally, chromatin condensation was reduced about 30% after feeding in python cardiomyocytes and confirmed by increased histone acetylation, indicating a predominant role for epigenetics in post-prandial adaptation. These results suggest that feeding promotes positive cardiac inotropy in python via a number of coordinated mechanisms to enhance energy production, increase myofibril and tissue compliance, and increase chromatin accessibility. As heart failure is commonly characterized by depressed contractility, compromised energetics, and increased tissue stiffness, assessing post-prandial adaptation in python hearts provides us with powerful insights that could inform the development of therapeutics for human heart diseases.

Ethical Engagement with Movies

In Screen Stories, Carl Plantinga concedes that films have considerable power to manipulate our emotions, attitudes, and even action tendencies. Still, he believes that film viewers do consciously engage in various types of cognition and judgment, and thus he argues that they can resist films’ manipulations. The “engaged critic” he calls for can assist in assessing how films create and convey their moral messages. I raise some questions about the account Plantinga gives of how both character engagement and narrative structures contribute to filmic manipulation. First, I note that there is an unresolved active/passive tension in his picture of film viewers. Second, I suggest that his treatment of narrative paradigm scenarios does not offer a strong enough account of the specifically filmic aspects of screen stories and how they differ from literary stories. And finally, I raise some questions about his ideal of the ethically engaged film critic and the social role to be played by such a critic.