Muscle Bio Week 11.docx

***Week 11, Module 11: Acute Molecular Responses to Resistance Exercise***   - RT results in less energetic demands and turnover of metabolic fuels. - This results in **less metabolic-type stress** within the active muscle fibres, and therefore less accumulation of markers of energy...

***Week 11, Module 11: Acute Molecular Responses to Resistance Exercise***   - RT results in less energetic demands and turnover of metabolic fuels. - This results in **less metabolic-type stress** within the active muscle fibres, and therefore less accumulation of markers of energy stress (such as changes in the AMP:ATP ratio, hydrogen ions (H+), and redox state (NAD+:NADH ratio).  - Instead, resistance exercise causes far greater** *mechanical-type stress*** on the active muscle fibres. Like the sensing of markers of energy stress, mechanical stress can also be*** detected ***by the muscle cell, and then communicated within the cell via signalling pathways that help the cell initiate an appropriate response, such as ***increasing protein synthesis rates*** and subsequently the ***size of muscle fibres*** (hypertrophy).   *The mTOR (Mechanistic Target or Rapamycin) Signalling Pathway* - This is a key signalling molecule that responds to resistance training and is key for hypertrophy. - It can be split into 2 types, both containing the mTOR protein and other associated proteins and each has distinct functions: 1. mTROC1: includes another regulatory protein know as raptor (regulatory associated protein of mTOR). 2. mTROC2: has a protein called rictor (rapamycin-insensitive companion of mTOR) - the two mTOR complexes also have distinct functions. The mTORC1 is considered a master regulator of cell growth and metabolism and is directly regulated by cellular energy status and nutrients, while the mTORC2 is not. Accordingly, mTORC1 promotes cell growth by positively regulating anabolic processes such as protein synthesis, while inhibiting catabolic processes such as protein breakdown.  - As the mTORC1 is the mTOR complex involved with the regulation of protein synthesis and cell growth, this module will solely focus on discussing the regulation of mTORC1.   *How is mTORC1 activated?* - Influenced by lots of upstream signals including mechanical stress, growth factors, nutrients and oxygen levels. - Rheb, a small protein, is a key player in activation. Interaction between the two appears to be a vital step in mTOC1 activation by all upstream signals. - As Rheb functions as an important upstream regulator of mTORC1, it follows that factors modulating Rheb activity also regulate mTORC1. The activity  of Rheb is controlled by the tuberous sclerosis complex 2 (TSC2, also known as Tuberin).  - Under resting conditions, TSC2 negatively interacts with Rheb, switching it to its inactive state, therefore blocking the activation of mTORC1.  - Conversely, in response to upstream signals such as mechanical loading and hormones/growth factors, the activity of TSC2 is inhibited, resulting in Rheb (and therefore mTORC1) activation. - Other signals such as amino acids also lead to mTORC1 activation, but via a different mechanism whereby mTORC1 is brought closer to the cellular location of its activator protein Rheb.   *Signals Leading to mTORC1 Activation* Growth Factors and Hormones - Insulin and IGF-1 can activate mTROC1. - Binding of growth factors to the insulin receptor then activates the PI3K/Akt pathway. Once active, this pathway leads to the phosphorylation and inhibition of the TSC2 protein complex, which is an inhibitor of an important activator of mTORC1 known as Rheb. - If there are no growth factors, the TSC2 complex interacts with Rheb and keeps it inactive. - However, in the presence of insulin/growth factors, a protein known as Akt phosphorylates and inactivates TSC2, causing it to move away from Rheb. This pathway therefore acts to remove the TSC2 complex away from its target (Rheb) so that mTORC1 can be switched on. - As you will see below, this is the same manner by which mechanical loading can activate mTORC1, but is slightly different from the way amino acids can activate mTORC1. - This is why mechanical loading (resistance exercise) and growth factors have little additive effect when combined together, but ingesting amino acids can have an additive effect when combined with resistance training. - However, in response to resistance exercise, mTORC1 becomes activated independent of the PI3K/Akt pathway (and therefore independent of insulin or other growth factors). Instead, mechanical stress associated with resistance exercise can directly activate mTORC1.   Mechanical Load - Important signal for muscle growth - mechanical load leads to mTORC1 activation via the phosphorylation of TSC2, and its removal away from the mTORC1 activator, Rheb - In resting muscle, TSC2 interacts with (and inhibits) Rheb. In response to mechanical stress, which is detected by sensors known as mechanoreceptors, TSC2 becomes phosphorylated and is moved away from Rheb, leading to mTORC1 activation.  - Unlike with insulin and growth factor stimulation, the kinase responsible for phosphorylating TSC2 in response to mechanical load does not appear to the Akt. Indeed, a number have studies have shown that mTORC1 can be activated in the absence of the PI3K/Akt pathway (meaning insulin or growth factors aren't required), although the kinase responsible for phosphorylating TSC2 in response to mechanical stress remains unidentified.   Amino Acids - RT causes increases in AAs, specifically leucine, concentration within the muscle cell, likely due to an increase in the amino acid transporter LAT1 - Amino acids activate mTORC1 with the involvement of Rheb but is distinct from insulin/IGF1. - Amino acids stimulate the movement of mTORC1 towards where Rheb is located in the cell, the lyosome. When mTORC1 and Rheb come together, it activates. - Amino acids also activate Rags, a small group of proteins, attached to the lyosome. When these are active, they attract mTORC1 to the lyosome, forcing it to come into contact with Rheb, leading to an increase in cellular protein synthesis rates.   *What does mTORC1 do when activated?* - It is a master regulator of cell growth. - It positive regulates anabolic processes and inhibits catabolic ones. - The most well-characterised substrates downstream of mTORC1 are p70S6K1 (p70 kDa ribosomal protein subunit kinase 1) and 4E-BP1 (eukaryotic initiation factor 4E binding protein 1) - **p70S6K1**: mTORC1 directly phosphorylates p70S6K1 at the Threonine 389 (Thr389) residue, and phosphorylation at this site is commonly used as a marker of mTORC1 activity. The importance of p70S6K1 in muscle hypertrophy is highlighted by studies showing correlations between post-exercise increases in p70S6K1 phosphorylation and muscle growth following long-term training in both rodents (Baar & Esser, 1999) and humans (Mayhew et al., 2011; Terzis et al., 2008). - **4E-BP1:** The activity of 4E-BP1 (eukaryotic initiation factor 4E binding protein 1), which acts as a repressor of translation initiation, is also controlled by mTORC1. When de-phosphorylated, 4E-BP1 strongly interacts (and interferes) with an important protein in translation initiation (known as eIF4E, or eukaryotic initiation factor 4E). The phosphorylation of 4E-BP1 by mTORC1 facilitates the disassociation of 4E-BP1 from eIF4E, thus relieving the inhibitory effect of 4E-BP1 on eIF4E and allowing translation initiation to occur. *Molecular Regulation of Skeletal Muscle Hypertrophy* - Skeletal muscle is constantly going through a turnover process, aka, muscle protein synthesis and muscle protein breakdown. - The net balance between synthesis and breakdown dictates the changes happening at the muscle fibres over time = hypertrophy or atrophy - RT is a strong stimulus for MPS and can remain elevated up to 24-48 hours post session. - If exercise is performed fasted, MPB rates are also elevated. - Ingestion of amino acids (i.e., protein), and specifically the essential amino acids (EAAs), which include leucine, can also independently increase MPS, as well as inhibit MPB. - Regular feeding during post-exercise recovery helps to maintain rates of MPS above that of MPB, leading to muscle growth over time   Role of Satellite Cells in Hypertrophy - Muscle fibre CSA is associated with the incorporation of new myonuclei originating from satellite cell populations. - Upon activation, satellite cells are incorporated as new nuclei within the muscle fibre and can then contribute to the production of new contractile proteins.  - However, the relative importance of satellite cell recruitment and post-exercise increases in MPS to skeletal muscle hypertrophy in response to resistance exercise is still hotly debated.  - Some studies have observed correlations between muscle fibre size and myonuclei number, supporting the idea that satellite cell recruitment occurs simultaneously with increases in muscle fibre size. However, whether satellite cell recruitment is essential for muscle fibre hypertrophy remains controversial, as experiments in mice show muscle hypertrophy is possible despite considerable (\>90%) reductions in satellite cell numbers.