Muscle Bio Week 3.docx

Muscle Bio Week 3 ***Week 3, Module 3: Fuel Delivery and Storage in Skeletal Muscle*** the metabolic rates seen in skeletal muscle are unmatched by any other tissue in the body, and can increase by as much as 200-fold during exercise. Therefore, the muscle cell (analogous to the F1 engine) is nece...

Muscle Bio Week 3 ***Week 3, Module 3: Fuel Delivery and Storage in Skeletal Muscle*** the metabolic rates seen in skeletal muscle are unmatched by any other tissue in the body, and can increase by as much as 200-fold during exercise. Therefore, the muscle cell (analogous to the F1 engine) is necessarily different from regular cells (analogous to the standard car engine) and is specifically designed to optimise fuel delivery to the sites of cellular energy production (i.e., the mitochondria). This allows the muscle cell to maintain a ***high rate of energy production*** to fuel exercise. Muscle cells (also known as ***myocytes***) must use both extracellular (sourced outside of the cell, such as blood glucose or lipids) and intracellular (sourced inside the cell, such as intramuscular glycogen, lipids, phosphocreatine, and stored ATP) substrates to fuel energy production.   *[Skeletal Muscle Structure: Key Terminology ]* Muscle cells are also known as ***myocytes***. The cell membrane of a muscle cell is known as the ***sarcolemma***, and the interior of the cell, the cytoplasm, is known as the ***sarcoplasm***. The sarcoplasm contains the usual subcellular structures (known as ***organelles***): - Nucleus, mitochondria, Golgi apparatus, lysosomes - A specialised version of the endoplasmic reticulum known as the ***sarcoplasmic reticulum*** In addition to these typical subcellular structures, muscle cells also contain a number of specialised structures designed to enhance the ability of muscle to produce and use energy for muscle contraction. These structures include: - ***Myofibrils*** that contain the contractile elements of the muscle cell (i.e., the sarcomeres) - ***T-tubules*** to enhance the function of the sarcoplasmic reticulum - ***Myoglobin** *(an oxygen storage and transport site) - Stored ***glycogen*** (in the form of glycogen granules) and stored ***triglycerides*** (in the form of lipid droplets) - ***Multiple nuclei*** per cell (as opposed to typical cells that contain a single nucleus)   [Mitochondria: The Site of Aerobic Energy Production ] - During aerobic metabolism, ATP production occurs within the mitochondria. This applies to both carb and fat sources of ATP. Both sources are then converted in Acetyl-CoA to then be broken down into fuel. - How well aerobic ATP production occurs is dependent on the number and size of the mitochondria, the capacity for oxygen transport to the muscle (via capillaries and the bloodstream supplying the muscle) and the storage of oxygen (determined by levels of cellular myoglobin). - Mitochondria within muscles are arranged in a continuous membrane system, aka mitochondrial reticulum. - They are the powerhouse of the cell   *Structural Features* - Inner membrane: impermeable to ions and polar molecules unless they\'ve got specific transporters - Outer membrane: encases the mitochondria and \'pores\' for ions and polar molecules - Cristae: increases the surface area of the inner membrane. - Intermembrane space: has enzymes related to the electron transport chain - Matrix: has enzymes of the Kreb Cycle and enzymes for fatty acid oxidation   There are 2 different types of mitochondria within muscles: 1. ***Subsarcolemmal mitochondria*** account for \~10-15% of total mitochondria, and are located near the sarcolemma (outer membrane of the myocyte). Their location near the sarcolemma suggests they are likely involved in ATP production for events occurring at the cell membrane, such as membrane transport (e.g., transporting circulating fatty acids into the cell) 2. ***Intermyofibrillar mitochondria*** are more abundant (85-90%) and are embedded among the myofibrils. They have higher rates of aerobic energy production than sarcolemmal mitochondria. This is because intermyofibrillar mitochondria are believed to provide energy primarily for the contractile apparatus (i.e., the sarcomeres), hence being important for muscle contraction.   [Delivery of Extracellular Fuels to Skeletal Muscle ] *Capillaries* - Delivers nutrients to and removes waste products from cells, including muscle cells. - The capillary bed constitutes a vast surface that facilitates exchange of oxygen, substrates and metabolites between blood and skeletal muscle.** **While the muscle microvasculature is optimally designed for the transfer of oxygen from the circulation to muscle cells, it is less efficient for the transfer of substrates. - Because of the lack of substantial oxygen stores in muscle, the oxygen required to meet energy demands has to be supplied by the circulation. By contrast, only a limited quantity of substrates is supplied from the circulation during exercise, due to the availability of intramuscular energy stores. - At exercise intensities above 30% VO2max, there is more reliance from the muscle on intracellular substrate stores, eg: glycogen. These stores eventually exhaust during exercise = onset of fatigue and diminished performance. These stores will replenish during rest or lower energy demands. - The rate of carb and fat transport are at max during low intensity exercise (40% VO2max) and can\'t be increased during high intensity exercise. At higher intestines, the muscles rely on the intracellular fuel stores, ie: glycogen and lipid stores in the cell. No more than 20-30% of fuel in the muscle comes from extracellular sources.   *T-Tubules* - Tunnel-like extensions of the sarcolemma, extending from one side of the cell layer to the other. - Allows for the end of the cell to be reached. - The first function of the t-tubules is to enable the movement of electrical charge from the cell surface to the internal areas of myofibres, triggering the release of calcium ions from the sarcoplasmic reticulum. Without t-tubules, electrical conduction into the interior of the cell would happen much more slowly, causing delays between neural stimulation and muscle contraction - resulting in slower, weaker contractions. - The t-tubules also play a role in substrate metabolism and contains a significant proportion of the insulin receptors and glucose transporters.** **The t-tubule network therefore allows glucose to be delivered in a targeted manner to the intracellular metabolic machinery within a skeletal muscle cell. - Substrates can be quickly carried to the centre of the muscle fibre where there are proteins to transport glucose (and presumably other substrates) across the t-tubule membrane to the site where it can be immediately used for energy or stored. [Intramuscular Fuel Stores ] - Mitochondria can consume fuel faster than the supply from external sources. - For contraction to be sustained, the muscle then relies on its internal stores. - Metabolic fuels within the muscle are pools of glycogen granules and lipid droplets.   *Glycogen* - Glycogen is a branched chain polymer containing many glucose sub units. A glycogen particle in a skeletal muscle can contain as much as 50,000 glucose molecules. - The amount of glycogen stored within the muscle is dependent on 3 things: a. Training status b. Basal metabolic rate c. Nutritional habits. - Muscle glycogen functions as an immediate reserve source of available glucose for muscle cells. As muscle cells lack the enzyme ***glucose-6-phosphatase***, which is required for glucose to be transferred back to the circulation, the glycogen stored in muscle is 'locked' inside the muscle cell for exclusive use, and is not shared with other cells. - Due to the reliance on glycogen in anaerobic glycolysis, the oxygen demand is low. - Glycogen availability is essential to power ATP resynthesis during high-intensity exercise, which relies heavily on glycogenolysis (the breakdown of glycogen into its component glucose molecules) to liberate the energy needed for ATP resynthesis. Reductions in muscle glycogen levels are associated with impaired exercise performance, even when there is sufficient amount of other fuels available. - Glycogen is often thought of as being uniformly distributed within the muscle cell. However, glycogen is actually distributed within the muscle fibre in ***distinct pools***, allowing glycogen to act as a metabolic fuel for different processes involved in muscle contraction: a. ***Subsarcolemmal glycogen***: located just [beneath] the sarcolemma (5-15% of glycogen stores) b. ***Intermyofibrillar glycogen***: located [between] the myofibrils, mainly at the level of the I-band close to mitochondria and sarcoplasmic reticulum (\~75-85% of glycogen stores), and c. ***Intramyofibrillar glycogen***: located [within] the myofibril, mainly near the Z-line of sarcomeres (5-15% of glycogen stores). - Due to being so close to the site of contraction and able to sustain high rates of ATP production, this is why it is the primary fuel for moderate to intense exercise. - The intramyofibrillar pool of glycogen influences calcium release from the SR. - impairments in muscle function during fatigue are associated with defective calcium release from the sarcoplasmic reticulum, this pool of glycogen plays a key role in limiting fatigue during exercise *Intramuscular Triglycerides* - Intramuscular triglycerides are mostly found in the cytoplasm of oxidative (type I) muscle fibres as lipid droplets. - These lipid droplets are located between the myofibrils and in close proximity to the mitochondria, therefore providing a readily-available source of fatty acids for energy production (via oxidative phosphorylation). - Lipid droplets in skeletal muscle are in direct contact with the outer mitochondrial membrane, which is often marked by a 'dent' in the mitochondria - It seems likely that the fatty acids are transported across the mitochondrial membrane within these areas of contact, allowing them to be more quickly transported into energy production sites.\ In skeletal muscle cells, IMTGs represents a fuel that can be either mobilised or stored depending on the cellular energy demand. - When energy demands increase, such as during exercise, the triglyceride can be broken down to glycerol and 3 fatty acid chains, in a process called ***hydrolysis***. The free fatty acid chains can then be used to fuel ATP production within the mitochondria.\ Conversely, when energy demands are low, free fatty acids (FFAs) can be combined with glycerol to form IMTGs via a process known as ***esterification***. This results in an increase in stored IMTGs that can be used later when required.