Muscle Bio Week 4.docx

***Week 4, Module 4: Fuel Transport into Skeletal Muscle*** [Transport Across the Cell Membrane ] - Cells are surrounded by a phospholipid membrane. This membrane has the hydrophilic head and the hydrophobic tails. - Phospholipids have 2 fatty acids instead of 3 and instead have a 3rd...

***Week 4, Module 4: Fuel Transport into Skeletal Muscle*** [Transport Across the Cell Membrane ] - Cells are surrounded by a phospholipid membrane. This membrane has the hydrophilic head and the hydrophobic tails. - Phospholipids have 2 fatty acids instead of 3 and instead have a 3rd carbon of glycerol that is part of the modified phosphate group. - The lipid bilayer is selectively permeable, only lipid substances can dissolve in the bilayer and move across without needing a transporter.   Types of proteins: 1. Receptor proteins: sensitive to specific chemicals in the ECF. Are responsive to hormones or ions depending on the situation. 2. Carrier proteins: move molecules across the cell membrane. The phospholipid bilayer is impermeable to water soluble molecules, so these proteins have to help them across.   Diffusion Molecules will naturally move from a region of high concentration to a region of low concentration, in a process called ***diffusion***. Diffusion is analogous to water flowing downhill -- there is no energy required for this process. If the molecule is polar/hydrophilic, then it needs the help of transporters or channels to get across the cell membrane. There is still no expenditure of energy as the molecule is flowing down its concentration gradient. This type of carrier-mediated transport is known as ***facilitated diffusion***. ***Carrier-mediated transport*** describes the use of proteins to help polar and/or very large molecules move across the cell membrane. The target molecule (also called the ligand) binds to a receptor site on the carrier protein, which causes the carrier protein to change shape and move the molecule to the inside of the cell membrane where it is then released.   [Fuel Transport into Skeletal Muscle ] The uptake of substrates works at 4 levels: 1. Energy demand by the contracting muscle 2. Delivery of substrates to the muscle 3. Transport of substrates into the muscle by specific transporters 4. Activation of the storage or metabolic pathways specific to the substrate, eg: glycogenesis for the storage of glucose as glycogen   - Increased metabolic demand from the working muscle is the driver for many physiological regulatory processes, eg: number of perfused capillaries and hormones affecting glucose and FFA into the bloodstream. - Max rate of substrate transport from capillaries to skeletal muscle seems to get reached at low intensity exercise. - At 40% VO2max, only 20-30% of fuels being used are coming from the circulation and doesn\'t increase with working intensity. This is when the body swaps to intracellular fuels as they are more readily available. - Changes to insulin also affects the availability of glucose and FFAs.   [Glucose Transport into Skeletal Muscle ] 3 main regulatory sites of glucose transport: 1. Glucose supply: via circulation. Dependent on blood supply to the muscle and the concentration of glucose in the blood. 2. Glucose transport: via facilitated diffusion, dependent on the presence of GLUT4 and GLUT1 (but this one to a lesser extent) in the surface membrane. 3. Glucose metabolism: storage of glucose as glycogen or the oxidation of glucose in the cell to generate energy in the form of ATP. This is what happens once glucose enters the cell, is either used for energy or stored as glycogen.   Video notes - The number of GLUT4 transporters in the membrane determines the level of transport of glucose into the cell - The content of GLUT4 in the cells can increase during exercise and after feeding - Insulin is secreted following eating food and increases the uptake of glucose. Insulin binds to the insulin receptor on the cell membrane, causing a structural change and triggering the GLUT4 to come to the membrane. From there, glucose is either used or stored. - Muscle contraction also triggers the presence of GLUT4. muscle contract alters the cellular energy state and triggers energy consuming pathways as well as the increase of metabolic by products. Because energy demands are higher during exercise, glucose is used as fuel instead of being stored as glycogen which would normally happening following feeding. - Insulin sensitivity is elevated for a number of hours following energy, glucose transport remains elevated for hours following exercise. In the post exercise period, glucose is rapidly stored as glycogen whilst fats are being used for energy.   *Muscle Glucose Uptake at Rest* - Under resting conditions, it is generally believed that glucose transport is the rate-limiting step for muscle glucose uptake, since GLUT1 expression is relatively low and the most of the GLUT4 resides within intracellular storage sites inside the muscle cell (excluded from the sarcolemma and T-tubules).   *Muscle Glucose Uptake after CHO Feeding* - Ingestion of a high-CHO meal increases the concentration of glucose in the circulation, which stimulates insulin secretion from the pancreas. Together these provide optimal conditions for muscle glucose uptake and glycogen synthesis.** **In skeletal muscle, an increase in circulating insulin stimulates what is known as the \'***insulin-dependent***\' pathway of glucose transport.** **Insulin commences its action by binding to its specific receptor on the cell membrane. The activation of the insulin receptor by insulin binding leads to a structural change in the receptor protein. This structural change then initiates a signalling cascade (a series of events whereby successive proteins are activation by one another) within the cell that ultimately leads to translocation of the glucose transporter GLUT4 to the plasma membrane, facilitating the glucose entry into the cell.   *Muscle Glucose Uptake DURING Exercise* - Muscle contraction increases GLUT4 from the intracellular sites to the sarcolemma and T tubules, thus increasing glucose transport. - It is referred to as the insulin independent pathway of muscle glucose uptake, as it acts independent to insulin and is stimulated by contraction. - Muscle contraction (i.e., exercise) alters the cellular energy state, resulting in an increased energy demand in the body. This triggers pathways that generate ATP, with a subsequent increase in the concentration of the by-products of these energy-generating processes. These factors signal that more fuel is required to power the replenishment of ATP. - The amount of blood flow to skeletal muscle can also increase by up to 20-times during intense, dynamic exercise (compared to rest), and there is also recruitment of capillaries which increases the available surface area for glucose and insulin delivery to the muscle. - The fate of glucose extracted from the blood is different in response to insulin and muscle contraction. During muscle contraction, the glucose stimulated to enter the muscle cell is used as a fuel source (oxidised), whereas the glucose is primarily stored in response to insulin. - It also appears there may be two intracellular pools of GLUT4 - one recruited primarily by insulin, and the other by muscle contraction. The existence of two pools of GLUT4 is perhaps one of the reasons for the finding that insulin and muscle contraction seem to have additive effects on glucose transport in muscle. *Muscle Glucose Uptake AFTER Exercise* - Post exercise, glucose transport and insulin sensitivity is elevated for hours. - This increase in insulin sensitivity allows insulin to stimulate more GLUT4 translocation, resulting in increased glucose uptake. - This means that post exercise, circulating glucose is quickly grabbed and stored by muscle, leaving fat to fuel the muscle energy requirements. Thus, glycogen replenishment after exercise is important.   [Fatty Acid Transport into Skeletal Muscle ] - Fats can enter via passive diffusion or a transporter. Transporters are the preferred method. - Regulated by transporters: - FAT/CD36: fatty acid translocase/cluster of differentiation 36 - FABPpm: plasma membrane associated fatty acid binding protein - FATP1 and FATP4: family of fatty acid transport proteins 1 and 4 - All transport proteins are present in skeletal muscle and all contribute to transport - The driving force behind fatty acid transport into muscle is the concentration gradient. The. Greater the amount of fatty acids between the blood and muscle, the greater the amount of FFAs that will move into the muscle - Insulin and muscle contraction also stimulate FFA uptake in the muscle. - There is evidence that suggests that CD36 and FATP4 are the most important - CD36 and FATP1 appear to be stimulated by insulin and muscle contraction   [Amino Acid Transport into Skeletal Muscle ] - Muscles are mostly made up of proteins, that are then comprise of amino acids. These are the building blocks. - There are 20 important amino acids and metabolism of them can be tricky. - Protein will only act as a fuel source when there is no carbs or fats left to use and the body is desperate. - Amino acid transporters: - SNAT2: sodium-coupled neutral amino acid transporter 2 - LAT1: L-type amino acid transporter 1 - PAT1: proton-assisted amino acid transporter 1 - CAT1: cationic amino acid transport 1 - Each transporter transports specific amino acids across the membrane. - If we want to build more proteins in the cell, we need to get more amino acids in. proteins are built through protein synthesis. - Ingestion of protein and amino acids and doing exercise are powerful stimulators of protein synthesis, this will peak at around 90 minutes - Muscle protein synthesis post feeding remains elevated above baseline for about 4 hours. - In response to exercise, there is an increase in transporters on the cell membrane, this increases in the intracellular pool of amino acids, thus allowing for an increase in protein synthesis. - The combination of amino acids and exercise enhances muscle protein synthesis in human skeletal above that stimulated by exercise or amino acid ingestion alone, lasting for up to 24 hours after exercise - Amino acid transporters are also associated with cellular signalling pathways related to muscle growth (hypertrophy) and muscle loss (atrophy). As such, in addition to facilitating the delivery of amino acids inside the muscle cell, some amino acid transporters have been identified as acting as membrane receptors (known as "***transceptors***"). - The most noted transceptor is SNAT2, which may sense changes in extracellular amino acid availability and possibly prime the cell for an influx of amino acids. - In human skeletal muscle, an increase in amino acid availability regulates muscle protein synthesis largely through the stimulation of the mechanistic target of rapamycin complex 1 (***mTORC1***) signalling pathway. Stimulation of the mTORC1 signalling pathway by amino acids results in an increase in the rate of muscle protein synthesis which, over time, can lead to skeletal muscle growth (hypertrophy)