Striated muscle tissue | EPFL Graph Search

Striated muscle tissue is a muscle tissue that features repeating functional units called sarcomeres. The presence of sarcomeres manifests as a series of bands visible along the muscle fibers, which is responsible for the striated appearance observed in microscopic images of this tissue. There are two types of striated muscle: Cardiac muscle (heart muscle) Skeletal muscle (muscle attached to the skeleton) Striated muscle tissue contains T-tubules which enables the release of calcium ions from the sarcoplasmic reticulum. Skeletal muscle includes skeletal muscle fibers, blood vessels, nerve fibers, and connective tissue. Skeletal muscle is wrapped in epimysium, allowing structural integrity of the muscle despite contractions. The perimysium organizes the muscle fibers, which are encased in collagen and endomysium, into fascicles. Each muscle fiber contains sarcolemma, sarcoplasm, and sarcoplasmic reticulum. The functional unit of a muscle fiber is called a sarcomere. Each muscle cell contains myofibrils composed of actin and myosin myofilaments repeated as a sarcomere. Many nuclei are present in each muscle cell placed at regular intervals beneath the sarcolemma. Based on their contractile and metabolic phenotypes, skeletal muscle can be classified as slow-oxidative (Type I) or fast-oxidative (Type II). Cardiac muscle lies between the epicardium and the endocardium in the heart. Cardiac muscle cells generally only contain one nucleus, located in the central region. They contain many mitochondria and myoglobin. Unlike skeletal muscle, cardiac muscle cells are unicellular. These cells are connected to each other by intercalated disks, which contain gap junctions and desmosomes. Unlike skeletal and cardiac muscle tissue, smooth muscle tissue is not striated since there are no sarcomeres present. Skeletal muscles are attached to some component of the skeleton, and smooth muscle is found in hollow structures such as the walls of intestines or blood vessels.

Targeting mitochondrial bioenergetics and NAD+ metabolism during sarcopenia and regeneration of skeletal muscle

Tanja Sonntag

The progressive decline of muscle mass and function called sarcopenia is a multi-factorial process associated to frailty, disability, and low quality of life in the elderly. The co-factor nicotinamide adenine dinucleotide (NAD+) becomes a limiting factor in the course of aging and other pathological conditions. It has emerged as a major regulator of cellular metabolism, which is modulated by dietary precursors of the vitamin B3 family. So far, no direct link between sarcopenia and alterations in NAD+ metabolism has been reported. In this thesis, I have taken a multi-disciplinary approach combining molecular profiling in humans and dietary and genetic manipulations in rodents to characterize the skeletal muscle NAD+ metabolism in the context of muscle plasticity and aging. We have performed a multi-center study to characterize the molecular signature of human sarcopenia compared to age-matched controls. Sarcopenic participants of three cohorts in Singapore, the United Kingdom and Jamaica presented a prominent transcriptional signature of mitochondrial dysfunction, which translated into functional bioenergetic deficiency with lower mitochondrial protein expression and activity. Furthermore, we established a concurrent decrease in NAD+ content of sarcopenic muscle, which correlated to lower muscle strength and function in these patients. Supplementation with the dietary NAD+ precursor nicotinamide riboside (NR) was shown to improve pathological muscle conditions and revert age-related mitochondrial dysfunction and stem cell senescence in mice. To test whether boosting NAD+ through NR can be beneficial in the context of sarcopenia, we investigated the acute response to NR supplementation in young adult and old sarcopenic rats. Acute NR treatment efficiently increased NAD+ levels and normalized specific age-related gene expression signatures in old rats, in particular related to fibrosis. Interestingly, our transcriptional profiling also revealed that the molecular response to NR is partially blunted in aging and suggests that aged muscle could be in a state of partial NAD+ resistance. To investigate the role of endogenous NR as NAD+ precursor in the muscle, we studied mice deficient for NR kinases 1 and 2 (NRK1/2 dKO), the rate-limiting enzymes for NR salvage. NRK1/2 dKO mice develop normally, but exhibit elevated salvage of the NAD+ precursor nicotinamide (NAM) to maintain tissue NAD+. Thus, our results demonstrate for the first time that an endogenous NRK-dependent flux actively converts NR into NAD+ in healthy skeletal muscle. Moreover, we demonstrated that NRKs are required for muscle regeneration, as dKO mice failed to efficiently regenerate the NAD+ pool during the active phases of myofiber remodeling, which coincided with a transient delay of myofiber maturation. Conversely, dietary NR improved the activation of muscle stem cells and accelerated recovery of NAD+ levels in regenerating myofibers of wild-type mice. Altogether, this work demonstrates that both in humans and preclinical models, sarcopenia is tightly linked to mitochondrial bioenergetics and NAD+ metabolism. Dietary manipulation of NAD+ levels is a promising therapeutic strategy for the management of age-related muscle dysfunction for which we uncovered important mechanistic insights linking metabolic fluxes through the NAD+ pathway to physiological adaptations.

EPFL2019

Mathematical modeling and numerical simulation of excitation-contraction phenomena in the heart

In this Master thesis we aim at studying some physiological and computational aspects of the excitation-contraction mechanisms in the heart muscle. This phenomenon exhibits many complexities at different spatio-temporal scales. The relevance and applicability of several recent phenomenological and physiologically detailed ionic models will be assessed. The choice of the treated models is based on an equilibrium between results that manage to reproduce correctly the complexity of the cardiac electrophysiology and a weak computational cost in order to solve the large set of ODEs which describe the dynamics of that ionic model. The preferred models include a large part of the more recent electrophysiological discoveries and understandings (e.g. L-type calcium and ryanodine channels) in order to reproduce at best the electrical conduction in the human cardiac tissue based on different experimental or computational measurements. According to these previous remarks, we will perform a thorough testing and quantitative comparison of these models and mechanical activation mechanisms in the framework of the LifeV finite element library. In a second step, a recent model for the description of crossbridge dynamics will be implemented. The importance of using good ionic models makes sense to identify correctly the possible influence on the muscle mechanics activation, which enable the heart to pump blood throughout the entire circulatory system.

2013

Reduced order models for the simulation of pathological heart valves

Lidia Stepanova

Numerical modeling of the human cardiovascular system (CVS) represents an active branch of research which allows the medical specialists to advance in understanding of underlined processes of blood circulation and the heart work at any scale, moreover, it helps to analyze the potential problems which can arise in the CVS by modifying the parameters inside the mathematical models. Due to inability to capture in details the pressure and flow parameters without invasion into heart chambers, the process of diagnosing heart diseases can become very complicated, the limited data on atrial pressure and cardiogram results can give only overall representation of the heart condition and the exactness of the diagnosis is based mainly on experience of the doctor. Nevertheless, the development of numerical models of CVS helps to get better understanding on processes which can cause particular disease (reverse flow leakage in heart chambers, improper contraction of heart muscles due to infarction of tissue). Mathematical model allows the analysis of all physical values of the system during the heart beat as well as possibility to adjust individual parameters specific to each patient. Therefore, it becomes an efficient tool for doctors to diagnose properly the heart disease, to assign the necessary treatment and surgery, and to predict the effect of implanting cardiac-assist devices.

2013

Targeting mitochondrial bioenergetics and NAD+ metabolism during sarcopenia and regeneration of skeletal muscle

Tanja Sonntag

EPFL2019