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Amplification curves generated in qPCR…
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Amplification curves generated in qPCR analysis with high amounts of target amplicons. The…
When people follow a diet and exercise plan, they may start to lose weight at a steady rate. However, many people reach a weight loss plateau, where their weight stays the same despite dietary changes and exercise.
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People can become frustrated when they hit a weight loss plateau, which can sometimes cause them to abandon their weight loss plan.
Most people are aware that weight loss requires them to burn more calories than they eat. However, many other factors also influence weight loss, including behavioral, hormonal, and environmental conditions.
Keep reading to learn more about why weight loss plateaus happen and what people can do to break through them.
When a person reaches a weight loss plateau, they will no longer lose any weight, despite following a diet and fitness regimen. Research shows that weight loss plateaus happen after about 6 months of following a low calorie diet.
Doctors are unsure why weight loss plateaus occur, but some theories include:
- the body adapts to weight loss and defends itself against further weight loss
- people stop following their diets after a few months
- the metabolism slows down if a person loses weight quickly
However, the researchers behind a study on this issue concluded that although a person’s metabolism can change as they lose weight, this does not explain why the weight loss plateau occurs. They believe that the weight loss plateau happens due to a person no longer adhering to their diet plan.
Sticking to a restrictive or low calorie diet plan every day can be challenging or, sometimes, unrealistic. Small, unconscious fluctuations in daily calories can cause early weight loss plateaus.
More research is necessary to determine why weight loss plateaus occur. Below, we cover some ways to break through them.
Recording meals and snacks can be tedious, but it can provide valuable insights.
Research shows that people tend to underestimate their energy or calorie intake significantly. Once people are fully aware of their eating and drinking patterns and understand where unnecessary calories are coming from, they can make changes.
The authors of an earlier study found that more than 50% of the participants underreported what they were eating. These participants had:
- higher body mass index (BMI)
- increased fat mass
- more visceral fat
- greater perceived stress levels
- a higher percentage of energy from protein
- lower levels of calcium, fiber, iron, vitamin B-1, and vitamin B-6
- fewer servings of fruits and vegetables
Keeping a food diary or using a food tracker app can help people see exactly how many calories they are consuming.
Some trackers even show whether people are getting enough or too much of one particular macronutrient, such as carbohydrate or fat.
Limiting or avoiding the intake of alcohol and sugary treats can help eliminate empty calories that do not provide nutritional value.
Exercise helps people maintain weight and build muscle, which can improve metabolism. How much exercise a person requires depends on many factors, including their weight and age.
The Physical Activity Guidelines for Americans recommend that adults do at least 150–300 minutes every week of moderate intensity exercise or 75–150 minutes of vigorous intensity activity.
Many people need more than 150 minutes of moderate exercise per week to maintain their body weight.
People who engage in more than 300 minutes of moderate physical activity every week and perform muscle strengthening activity of moderate intensity can experience additional benefits.
When a person starts dieting and exercising, their fitness level will improve. Over time, they may reach a certain level of fitness that allows them to progress to higher levels of activity. Throughout a person’s weight loss journey, they may need to adjust the intensity of their workout to continue to see results.
Introducing small, progressive changes in activity level can help people break through a weight loss plateau.
Studies have shown that reducing stress levels can help people lose weight.
In one study, researchers followed two groups of people with obesity. One group received advice on a healthful lifestyle and participated in a stress management program, and the second group only received the advice.
The participants in the stress management group experienced a more significant reduction in BMI than those in the control group.
The stress management strategies in the study included:
- diaphragmatic breathing
- progressive muscle relaxation
- guided visualization
A study that featured in the International Journal of Obesity found that sleeping for the same number of hours — and an adequate number of hours — improved weight loss outcomes.
People who slept for less than 6 hours a night had smaller changes in waist circumference compared with people who slept for 7–9 hours.
Improving sleep duration and quality may allow someone to break through a weight loss plateau.
Researchers have shown that people in the United States eat only about half of the daily fiber recommendation. People who follow low carbohydrate diets are eating even less fiber.
Fruits, vegetables, whole grains, and legumes are all rich in fiber and may be helpful for people who have reached a weight loss plateau.
Making small changes, such as replacing a daily glass of juice with a whole fruit, can help a person increase their fiber intake.
Many people do not consume enough vegetables on a regular basis. Vegetables are generally low calorie foods that can help people reduce their overall energy intake.
A 2018 review of studies found moderate-quality evidence that consuming more vegetables reduced the risk of weight gain and obesity.
The authors also noted that diets high in fruits and vegetables could lower people’s risk of preventable diseases.
Vegetables are high in fiber and water content, which may help people feel full and reduce the urge to overeat or eat foods with fewer nutrients.
Diets containing plenty of vegetables may be easier to follow because they encourage the higher consumption of specific foods rather than the restriction of certain types of food.
Hitting a weight loss plateau can be discouraging, but a person can often adapt their diet or fitness routine to continue to lose weight.
Recording their daily calorie intake can help people identify dietary issues, while increasing exercise intensity may challenge their body and help them burn more calories.
Getting enough sleep and reducing stress levels can also help a person break through a weight loss plateau.
Anyone who feels as though they have hit a weight loss plateau may wish to speak with a dietitian, certified personal trainer, or doctor.
The heart muscle is remarkable. At an average heart rate of 70 beats min−1, the heart needs to contract and relax more than 100 000 times a day without stopping or tiring. The rate and strength of these contractions must vary to meet physiological and pathological challenges. This article provides an overview of cardiac muscle physiology. We describe the structure of the cardiac myocyte, the generation and spread of the cardiac action potential, the process of excitation-contraction coupling, and the metabolism and energetics of the heart. Finally, we discuss the mechanics of muscle fibre contraction.
Structure of the cardiac myocyte
Each cardiac myocyte is surrounded by a cell membrane called the sarcolemma and contains one nucleus. The cells are packed with mitochondria to provide the steady supply of ATP required to sustain cardiac contraction. As with skeletal muscle, cardiac myocytes contain the contractile proteins actin (thin filaments) and myosin (thick filaments) together with the regulatory proteins troponin and tropomyosin. Cardiac muscle is striated, although the pattern is not as ordered as in skeletal muscle.
Fig. 1 shows the arrangement of the thick and thin filaments. The myofilaments within the myocyte are surrounded by sleeves of sarcoplasmic reticulum, analogous to endoplasmic reticulum found in other cells. Separate tubular structures, the transverse tubules (T tubules), cross the cell. In the cardiac myocyte, the T tubule crosses at the Z-line, in contrast to the A-I junction in skeletal muscle. The lumen of the T tubule is continuous with the extracellular fluid surrounding the cell and, as in skeletal muscle, the action potential is propagated down the T tubule. Adjacent cardiac myocytes are joined end-to-end at structures known as intercalated disks. These always occur at a Z-line. At these points, the cell membranes form a number of parallel folds and are tightly held together by desmosomes. This results in strong cell-to-cell cohesion, thus allowing the contraction of one myocyte to be transmitted axially to the next. Gap junctions exist between cardiac muscle cells, providing low resistance pathways for the spread of excitation from one cell to another.
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Schematic representation of a contractile unit in cardiac muscle. The actin filaments are anchored at the Z-line, myosin filaments are connected at the M-line. A sarcomere extends from one Z-line to the next.
Resting membrane and action potentials
Cardiac myocytes can be divided into work cells and pacemaker cells. The work cells have a large stable resting membrane potential and display a prolonged action potential with a plateau phase. The pacemaker cells have smaller unstable resting potentials and spontaneously depolarize, generating the intrinsic electrical activity of the heart. Pacemaker cells are found in the sinoatrial (SA) and atrioventricular (AV) nodes. The cells of the bundle of His and some Purkinje cells are also capable of spontaneous firing.
The cardiac action potential
The cardiac action potential is very different to that seen in nerves. It has a prolonged plateau phase lasting around 300 ms compared with 1 ms in nerves. The cardiac action potential has five phases as shown in Fig. 2. During phase 0, membrane permeability to potassium decreases and fast sodium channels open, producing rapid depolarization from −90 mV to +10 mV. During phase 1, there is partial repolarization, because of a decrease in sodium permeability. Phase 2 is the plateau phase of the cardiac action potential. Membrane permeability to calcium increases during this phase, maintaining depolarization and prolonging the action potential. Membrane permeability to calcium decreases somewhat towards the end of phase 2, and the plateau is partially maintained by an inward sodium current. Sodium flows into the cell through the sodium–calcium exchanger. The exchanger transfers three sodium ions into the cell in exchange for one calcium ion flowing out, and so produces a net inward positive current. As calcium channels inactivate towards the end of the plateau phase, an inward potassium current produces repolarization in phase 3. The resting membrane potential in phase 4 is approximately −90 mV. This is produced mainly by the selective permeability of the cell membrane to potassium and the concentration gradient for potassium that exists across the cell membrane and is close to the Nernst equilibrium potential for potassium.
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The cardiac action potential. Phase 0—depolarization because of the opening of fast sodium channels. Potassium flux also decreases. Phase 1—partial repolarization because of a rapid decrease in sodium ion passage as fast sodium channels close. Phase 2—plateau phase in which the movement of calcium ions out of the cell, maintains depolarization. Phase 3—repolarization, sodium, and calcium channels all close and membrane potential returns to baseline. Phase 4—resting membrane potential (−90 mV), resulting from the activity of the Na+/K+ ATPase pump which creates a negative intracellular potential because of the exchange of three sodium ions for only two potassium ions.
Much of the calcium influx in the plateau phase occurs through L-type (long opening) calcium channels. Increased activation of L-type channels occurs with catecholamine exposure, whilst they are blocked by calcium channel antagonists such as verapamil.
The cardiac action potential lasts about 300 ms. For the vast majority of this time, the cell is absolutely refractory to further stimulation. In other words, a further action potential will not be generated until repolarization is virtually complete. This prevents tetany from occurring. If a supramaximal stimulus occurs during the relative refractory period, the resultant action potential has a slower rate of depolarization and is of smaller amplitude than normal, producing a much weaker contraction than normal.
The pacemaker potential
The pacemaker potential is seen in cells in the SA and AV nodes. As shown in Fig. 3, it differs from the action potential of cardiac myocytes in that phases 1 and 2 are absent. The heart displays autorhythmicity: a denervated heart (such as the heart of a cardiac transplant patient) continues to contract spontaneously. Pacemaker cells do not have a stable resting action potential, and it is the spontaneous depolarization of the pacemaker potential that gives the heart its auto-rhythmicity. The pacemaker potential is produced by a decrease in membrane permeability to potassium, a slow inward current because of calcium influx via T-type (transient) calcium channels, and an increased sodium current because of sodium–calcium exchange. Once the threshold potential is reached, L-type calcium channels open, calcium ions enter the cell, and depolarization occurs. In contrast to the cardiac myocyte action potential, there is no inward movement of sodium ions during depolarization. Repolarization (phase 3 of the action potential) occurs because of an increase in potassium permeability. At the SA node, potassium permeability can be further enhanced by vagal stimulation. This has the effect of hyperpolarizing the cell and reducing the rate of firing. Sympathetic stimulation has the opposite effect.
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The pacemaker potential. Phases 1 and 2 do not occur. Phase 4—pacemaker potential. Because of slow inward current of sodium and a voltage gated increase in calcium conductance (via T channels) Phase 0—depolarization. As opposed to the ventricular muscle action potential, this occurs because of voltage gated calcium channels opening. Phase 3—repolarization. This is because of a decrease in potassium.
Rate, conduction, and speed
The SA node, other atrial centres, AV node, and bundle of His all have inherent pacemaker activity. The SA node has the highest rate of spontaneous depolarization and therefore suppresses the other pacemakers. In the denervated heart, the SA node discharges at a rate of approximately 100 times min−1. Vagal tone leads to a lower heart rate in healthy subjects at rest. From the SA node, impulses spread throughout the atria to the AV node at a rate of 1 m s−1. The AV node is the only means of electrical connection between the atria and the ventricles. Conduction here is slow (approximately 0.05 m s−1). This means that the AV node will only transmit a maximum of 220 impulses min−1, so protecting the ventricles from high rates of atrial depolarization.
Depolarization spreads from the AV node to the bundle of His in the interventricular septum. The bundle splits into right and left bundle branches, supplying the respective ventricles. The left bundle itself divides into anterior and posterior divisions. From the bundle branches, impulses travel through the ventricular muscle via a network of Purkinje fibres, at a velocity of 1–4 m s−1. The conducting system is arranged so that the apices of the ventricles contract before the bases, propelling blood out of the chambers.
Excitation contraction coupling
This is the process linking electrical excitation to contraction. Calcium has an essential role in this process; a raised intracellular calcium concentration is the trigger that activates contraction. An understanding of calcium handling is essential to understanding the function of the heart. The intracellular calcium ion concentration in the cardiac myocyte at rest is 0.0001 mM litre−1 and that in the extracellular fluid is 1.2 mM litre−1. During the plateau phase of the action potential, calcium ions flow down this steep concentration gradient and enter the myocyte. Most of this calcium enters through the L-type channels, located primarily at sarcolemmal/sarcoplasmic reticulum junctions. The influx of calcium triggers the release of further calcium from the sarcoplasmic reticulum via ryanodine receptors. This calcium-triggered calcium release is in contrast to skeletal muscle, where the action potential triggers calcium release directly.
Free intracellular calcium interacts with the C subunit of troponin. This leads to a configuration change in the troponin/tropomyosin complex, allowing actin to interact with myosin. Cross bridge cycling occurs, leading to a shortening of the sarcomere and resultant muscular contraction. As intracellular calcium concentrations decrease during repolarization, calcium dissociates from troponin as intracellular calcium concentration decreases, resulting in relaxation. Diastolic relaxation is an active (ATP-dependent) process. Calcium transport out of the cytosol occurs via a sarcoplasmic reticulum Ca2+-ATPase, through sarcolemmal Na+/Ca2+ exchange, via a sarcolemmal Ca2+-ATPase, and finally by utilizing a mitochondrial Ca2+ uniport.
The strength of a contraction may be varied by increasing the amount of free intracellular calcium, by altering the sensitivity of the myofilaments to calcium, or both. The latter occurs during stretching of the myofilaments and is responsible for the Frank–Starling mechanism (discussed later). Myofilament calcium sensitivity is reduced by acidosis. High concentrations of phosphate and magnesium also impair cardiac function.
Catecholamines activate beta-adrenergic receptors in the heart to produce a G-protein mediated increase in cAMP and enhanced activity of a cAMP-dependent protein kinase. This leads to the phosphorylation of calcium membrane channels, enhancing calcium entry into the cell. Phosphorylation of myosin also occurs, increasing the rate of cross bridge cycling. Catecholamines also increase the rate of re-uptake of calcium into the sarcoplasmic reticulum, thus aiding relaxation.
Metabolism and energetics
The oxygen consumption of the beating heart is on average 9 ml per 100 g min−1 at rest. This increases during exercise. Oxygen extraction from blood in the coronary circulation is high; therefore, an increase in oxygen demand must be met by an increase in coronary blood flow.
The heart is very versatile in its use of metabolic substrates. Carbohydrate utilization accounts for 35–40% of total oxygen consumption. Glucose and lactate are used in roughly equal proportions. A small amount of energy may be derived from ketones; however, 60% of the basal energy requirement is provided by fat. The proportion of substrates utilized may vary depending on the nutritional state of the person. After a large meal containing glucose, more pyruvate and lactate are used. During periods of starvation, more fat is utilized. Insulin enhances glucose uptake into cardiac myocytes, and in untreated diabetes proportionally more fat is utilized. Normally <1% of the energy used by the myocardium is produced by anaerobic metabolism. This proportion increases during periods of hypoxaemia; however, lactic acidosis impairs myocardial function and can ultimately lead to myocardial cell death.
Contraction of the isolated muscle strip
The mechanics of cardiac myocyte contraction can be studied in the laboratory by examining the behaviour of an isolated muscle strip (Fig. 4). The papillary muscle is convenient for this as its fibres run in roughly the same direction. The muscle is placed under an initial tension or preload. If the muscle strip is anchored at both ends and stimulated it undergoes isometric contraction. The tension generated during isometric contraction increases with increasing initial length (Fig. 4a). Alteration in initial fibre length is analogous to preload. Increasing venous return to the heart results in an increased left ventricular end diastolic volume, thereby increasing fibre length. This produces an increase in the force of contraction and an increased stroke volume resulting in the familiar Starling curve. The conventional explanation for this is that at normal resting length, the overlap of actin and myosin is not optimal. Increasing the initial length improves the degree of overlap and therefore increases the tension developed. It has become clear in recent years that this mechanism is unlikely to account for the shape of the Starling curve under physiological conditions. Several other possible mechanisms have been implicated. Lengthening the muscle increases the sensitivity of troponin to calcium (length-dependent calcium sensitivity) and can also lead to enhanced intracellular free calcium.
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Contractile properties of myocardial muscle. Left: Simplified arrangement to study contraction of isolated cat papillary muscle. In isotonic contractions the weight labelled ‘afterload’ is picked up as soon as shortening begins. The weight labelled preload sets the resting length. If the preload is clamped in place contraction becomes isometric. Right: Three fundamental relations: (a) isometric contraction at increasing lengths, (b and c) isotonic contractions beginning from two different resting lengths (8 and 10 mm). Contractile force, velocity, and shortening are all increased by stretching the relaxed muscle.3
If the muscle is able to shorten, but has to lift a weight, this is known as isotonic contraction. The weight moved by the muscle strip represents afterload. As afterload increases, both the amount and velocity of shortening decreases (Fig. 4b and c). Conversely, reducing the afterload enhances shortening, a fact of considerable importance in the management of the failing heart. If the preload is increased by stretching the muscle and the experiment repeated, both velocity and shortening are enhanced. (Fig. 4b and c).
In vivo, the initial phase of cardiac contraction, from the closure of the mitral and tricuspid valves to the opening of the aortic and pulmonary valves, is isotonic. Tension is developed, but the ventricle does not eject blood, as there is no muscle fibre shortening. After the opening of the aortic and pulmonary valves, contraction becomes isotonic, tension is maintained, but blood is ejected and tonic shortening occurs.
In vitro, perfusing papillary muscles with norepinephrine increases the strength and rapidity of the isometric contraction. This increased contractility (i.e. an increased force of contraction for a given fibre length) occurs in vivo after sympathetic stimulation and release of catecholamines. As mentioned earlier, catecholamines may augment both contraction and relaxation of cardiac muscle. However, as catecholamines increase the intracellular calcium load, more energy is required to fuel the pumps that sequester the calcium in diastole. In a failing myocardium, energy demand may outstrip supply (e.g. because of fixed coronary stenoses) and the addition of catecholamines may result in impaired diastolic relaxation. Levosimendan is a new drug that increases the sensitivity of troponin to calcium such that the heart performs better with lower intracellular calcium concentrations. Less energy is then required in diastole to reduce intracellular calcium concentrations.