Muscle Bio Week 9.docx

***Week 9, Module 9: Introduction to Cell Signalling and Exercise***   - Contraction of skeletal muscle disrupts homeostasis. An appropriate response is developed and adaptations then occur to help minimise future disruptions to homeostasis. - Following exercise and ***muscle contract...

***Week 9, Module 9: Introduction to Cell Signalling and Exercise***   - Contraction of skeletal muscle disrupts homeostasis. An appropriate response is developed and adaptations then occur to help minimise future disruptions to homeostasis. - Following exercise and ***muscle contraction***, both extracellular (e.g., hormones, mechanical load) and intracellular (e.g., changes in the cellular concentrations of AMP, ATP, oxygen, and reactive oxygen species) ***signals*** are rapidly '***sensed***' by skeletal muscle. This leads to intracellular ***signal transduction*** or the activation of "signalling cascades", which communicate the exercise signal within the muscle cell and ultimately lead to altered gene expression, and eventually translation to protein and functional adaptation of the cell. This process is termed "***regulated transcription***". - Importantly, the default state of transcription in humans is "off", which means that unless transcription is turned on, gene expression cannot occur. Once activated by muscle contraction and the sensing of primary signals, any signalling cascades result in the activation of transcription factors, which can bind to specific DNA sequences and activate transcription, thereby ***regulating gene expression***   *Cell Signalling Basics* - Cell signalling is an important communication mechanism within the cells. - It links the incoming info of what is disturbing homeostasis with then how to appropriately respond to it. Be generating the right response, it will then lead to adaptations to prevent disruption in the future.   Phosphorylation - This is the addition of a phosphate group to a protein on a phosphate accepting amino acid. In humans this normally happens on the amino acids serine, threonine and tyrosine. - Phosphorylation is a form of post translational modification as the protein is altered after it has been synthesised/translated. - Kinases, which aid in the transfer of phosphate to another molecule, belong to a group of enzymes called phosphotransferases. Phosphotransferases aid in the addition of the phosphate from an inorganic phosphate (e.g., ATP) to the acceptor molecule - Many molecules are energy donors that serve to supply the phosphate group, including ATP. Phosphorylation prepares molecules for the tasks they need to perform   Dephosphorylation - Occurs when this phosphate group \"falls off\" or is removed once the protein has done what it needs to do - Phosphatases act to remove the phosphate from the phosphorylated molecules - Phosphorylation plays an important role in cell signalling, by altering (increasing or decreasing) the rate of activity of enzymes. This begins a cascade of events (e.g., protein A phosphorylates protein B, protein B phosphorylates protein C, etc.), eventually leading to changes in gene expression and therefore protein content   *Linking Exercise Signals to Physiological Adaptation* Primary Signals, Signalling Cascades and Gene/Protein Expression - The signal transduction process associated with exercise is as follows: 1. Muscle contraction during exercise results in a range of metabolic (breakdown of metabolic fuels) and mechanical (muscle stretch or damage) stimuli within the contracting muscle 2. For example, increased turnover of ATP lead to increases in ADP and AMP, oxidation of metabolic fuels in the mitochondria produce reactive oxygen species (ROS), and normal contractile function results in the release of calcium from the sarcoplasmic reticulum 3. All of these metabolic by-products activate signalling molecules (or sensors), including protein kinases and phosphatases 4. From there, these sensors are integrated into signal transduction pathways that activate transcription factors and transcriptional co-regulators, ultimately leading to changes in the expression and/or repression of specific genes, and the accumulation of specific proteins (and hence adaptation) over time   Timing of Cellular Responses to Exercise -  the process of transcription (i.e., creating more mRNA) occurs transiently following exercise. A given bout of exercise elicits a rapid increase in relative mRNA expression of a given gene, which is typically greatest at 3--12 hours after exercise and generally returns to basal levels within 24 hours. - mRNA response following excessive exercise is decreased, explaining the concept of diminishing returns and why progressive overload is important. However, a single bout of exercise only isn\'t enough to stimulate structural or functional changes - In response to single exercise bouts, elevated rates of post-exercise protein synthesis cause relatively modest increases in protein content, whereas repeated exercise bouts results in the gradual accumulation of proteins in response to repeated \'pulses\' of increased gene (mRNA) expression.  - Long-term adaptations to training are therefore due to the cumulative effects of each individual exercise session, whereby changes in protein content or enzyme function can result in improved exercise performance and whole muscle metabolism