Week 11: Acute Molecular Responses to Resistance Exercise

Muscle Synthesis and Breakdown

• The balance of muscle protein synthesis (MPS) and muscle protein breakdown (MPB) determines muscle growth (hypertrophy) or loss (atrophy).
• Resistance training (RT) significantly stimulates MPS, with elevated effects lasting up to 24-48 hours post-exercise.
• Fasted exercise results in increased MPB rates.
• Essential amino acids (EAAs), particularly leucine, can enhance MPS and inhibit MPB when consumed post-exercise.
• Regular nutrient intake during recovery is important to sustain MPS above MPB, promoting muscle growth over time.

Role of Satellite Cells in Hypertrophy

• Muscle fiber cross-sectional area (CSA) increases through the incorporation of new myonuclei from satellite cells.
• Activated satellite cells integrate into muscle fibers, contributing to new contractile protein production.
• The significance of satellite cell involvement in resistance exercise-induced hypertrophy remains debated.
• Some studies suggest connections between muscle fiber size and myonuclei number, indicating simultaneous recruitment and muscle size increases.
• Mouse studies demonstrate muscle hypertrophy can occur with over 90% reduction in satellite cell numbers, raising questions about their essentiality in hypertrophy.

Acute Molecular Responses to Resistance Exercise

• Resistance training has lower energy demands compared to other exercises, leading to reduced stress markers like AMP:ATP ratio and hydrogen ions.
• Mechanical stress from RT leads to hypertrophy through cellular signaling pathways that enhance protein synthesis rates.

mTOR (Mechanistic Target of Rapamycin) Signalling Pathway

• mTOR is central to the response of resistance training and muscle hypertrophy regulation.
• Two mTOR complexes exist: mTORC1 (with raptor) and mTORC2 (with rictor), each serving distinct roles.
• mTORC1 regulates cell growth and metabolism, influenced by cellular energy and nutrients, promoting protein synthesis while inhibiting breakdown.
• mTORC1 activation occurs when it interacts with Rheb; amino acids also facilitate this process by recruiting mTORC1 to lysosomes.

Functions of Activated mTORC1

• Acts as a master regulator of cell growth, positively influencing anabolic processes and inhibiting catabolic ones.
• Main downstream substrates of mTORC1 include p70S6K1 and 4E-BP1.
• p70S6K1 is phosphorylated by mTORC1, with phosphorylation at Thr389 serving as an activity marker; correlations exist between its phosphorylation post-exercise and muscle growth.
• 4E-BP1 inhibits translation initiation; mTORC1 phosphorylation signals its disassociation from eIF4E, thus promoting translation initiation and protein synthesis.

Muscle Turnover Dynamics

• Skeletal muscle continually undergoes protein synthesis and breakdown, involved in maintaining muscle health and responding to exercise stimuli.

Activation of mTORC1

• mTORC1 is activated by various upstream signals: mechanical stress, growth factors, nutrients, and oxygen levels.
• Rheb, a small GTPase, is crucial for mTORC1 activation; its interaction with mTORC1 is essential for response to upstream signals.
• TSC2 (Tuberin) negatively regulates Rheb under resting conditions, preventing mTORC1 activation.
• On receiving signals like mechanical loading or hormones, TSC2 is inhibited, allowing Rheb to activate mTORC1.

Signals Leading to mTORC1 Activation

Growth Factors and Hormones

• Insulin and IGF-1 are effective at activating mTORC1.
• Growth factor binding to the insulin receptor activates the PI3K/Akt pathway, leading to TSC2 phosphorylation and inactivation.
• Without growth factors, TSC2 keeps Rheb inactive; with growth factors, Akt inactivates TSC2, enabling mTORC1 activation.
• Mechanical loading and growth factors both activate mTORC1 by similar mechanisms but differ from amino acid-induced activation.
• Resistance exercise activates mTORC1 independently of the PI3K/Akt pathway, directly triggering mTORC1 through mechanical stress.

Mechanical Load

• Mechanical stress is a critical signal for promoting muscle growth.
• It activates mTORC1 by phosphorylating TSC2, thus relocating it away from Rheb.
• In resting muscle, TSC2 inhibits Rheb, but mechanical stress activates sensors (mechanoreceptors) that phosphorylate TSC2 for mTORC1 activation.
• The kinase responsible for TSC2 phosphorylation in response to mechanical load is unidentified, distinct from Akt.

Amino Acids

• Resistance training increases amino acids (especially leucine) levels in muscle cells via transporter LAT1.
• Amino acids activate mTORC1 through Rheb but via different mechanisms compared to insulin/IGF-1.
• They drive mTORC1 towards lysosomes, where it encounters Rheb for activation.
• Active Rag proteins, associated with lysosomes, help recruit mTORC1 to Rheb, increasing protein synthesis.

Functions of Activated mTORC1

• mTORC1 acts as a master regulator of cell growth, promoting anabolic processes and inhibiting catabolic ones.
• Key substrates regulated by mTORC1 include p70S6K1 and 4E-BP1.

p70S6K1

• mTORC1 directly phosphorylates p70S6K1 at Threonine 389, serving as a marker for mTORC1 activity.
• Increased p70S6K1 phosphorylation correlates with muscle growth post-exercise in both animals and humans.

4E-BP1

• 4E-BP1 regulates translation initiation by interacting with eIF4E, an essential protein in the process.
• When phosphorylated by mTORC1, 4E-BP1 releases eIF4E, allowing for the initiation of translation.

Molecular Regulation of Skeletal Muscle Hypertrophy

• Skeletal muscle undergoes continuous turnover, balancing muscle protein synthesis and breakdown.

mTORC1 Activation and Function

• mTORC1, when activated by Rheb, plays a crucial role in cell growth regulation.
• Positive regulation of anabolic processes and inhibition of catabolic processes are significant functions of mTORC1.
• Key substrates influenced by mTORC1 include p70S6K1 and 4E-BP1.

Key Substrates of mTORC1

• p70S6K1:
  • Phosphorylated by mTORC1 at Thr389, marking mTORC1 activity.
  • Correlations exist between increased p70S6K1 phosphorylation post-exercise and muscle growth in both rodents and humans.
• 4E-BP1:
  • Acts as a translation initiation repressor.
  • When phosphorylated by mTORC1, it releases eIF4E, enabling translation initiation.

Muscle Protein Turnover

• Muscle undergoes continuous protein synthesis and breakdown, crucial for muscle health.
• The balance of synthesis and breakdown determines whether muscle hypertrophy or atrophy occurs.
• Resistance training (RT) significantly boosts muscle protein synthesis (MPS) for up to 48 hours post-exercise.
• Consuming essential amino acids (EAAs), especially leucine, can stimulate MPS and suppress muscle protein breakdown (MPB).

Role of Satellite Cells in Hypertrophy

• Muscle fiber cross-sectional area (CSA) growth correlates with new myonuclei from satellite cells.
• Activated satellite cells integrate into muscle fibers, aiding in contractile protein production.
• Debate continues on the essential role of satellite cell recruitment versus post-exercise MPS in muscle hypertrophy.

Impact of Resistance Training on Muscle Stress

• Resistance training leads to lower energy demands in muscle fibers, reducing metabolic stress markers (AMP:ATP ratio, hydrogen ions).
• Instead, it induces greater mechanical stress, triggering signaling pathways that facilitate protein synthesis and muscle fiber hypertrophy.

mTOR Signaling Pathway

• mTOR signaling is critical in response to resistance training, subdivided into two complexes: mTORC1 and mTORC2.
• mTORC1:
  • Contains raptor and regulates protein synthesis and cell growth based on nutrient and energy status.
• mTORC2:
  • Contains rictor, functions independently of cellular energy status, and is primarily associated with responses other than anabolic regulation.

Summary of mTORC1's Role

• mTORC1 serves as a master regulator of anabolic metabolism, primarily influencing protein synthesis and inhibiting protein degradation.
• Focus on mTORC1 is essential for understanding muscle hypertrophy mechanisms and responses to resistance exercise.