Cell Signaling and Resistance Training

Self-Signaling Responses with Resistance Training

Introduction

  • The focus is on key signaling pathways involved in resistance training and factors influencing them.
  • The goal is to understand the impact of training and nutrition on physiological and performance responses.

Overview of Cell Signaling

  • Acute response to exercise (Red): Muscle contraction leads to mechanical loads and metabolite accumulation.
    • Release of signaling molecules (hormones, myokines, growth factors).
    • Modulation of cell signaling pathways and altered enzyme activity.
    • Changes in cellular metabolism and altered gene expression.
  • Recovery after exercise (Blue): Modified synthesis of structural and enzyme proteins.
    • Tissue regeneration and satellite cell activation.
    • Replenishment of energy stores.
  • Chronic responses (Green): Positive net protein synthesis and protein accretion.
    • Selective muscle hypertrophy leads to increased muscle strength, size, and function.
    • Improved physical performance.
  • Nutrition impacts responses at various levels: signaling molecules, cell signaling pathways, and muscle protein synthesis rates.

Key Pathways

  • Mechanical strain and signaling molecules (hormones, myokines, growth factors) impact pathways like PA, FAK, and AKT. The AKT pathway stimulates mTOR.
    • Stimulating mTOR activates P70 S6K and inhibits 4E BP1 and ULK1.
    • mTOR Activation: Facilitates protein synthesis and inhibits protein degradation, resulting in an increase in muscle cross-sectional area.
  • Amino acids positively impact the mTOR pathway and muscle protein synthesis.
AMPK Pathway
  • High amounts of contractions or energy distress (poor fuel status or hypoxia) stimulate the AMPK pathway.
    • Increased calcium release and AMP to ATP ratio.
    • Stimulation of AMPK increases glucose uptake and mitochondrial biogenesis.
    • However, AMPK can stimulate FOXO signaling and ULK1, leading to increased protein degradation.

AMPK vs. mTOR

  • Up-regulation of AMPK activity: High AMP to ATP ratio, low ATP/glucose availability (starvation, fasting, inadequate nutrition), endurance training.
    • Down-regulation of mTOR activity.
  • Down-regulation of AMPK activity: Adequate ATP, fed conditions, insulin/IGF-1, resistance training, amino acid availability (especially leucine).
    • Up-regulation of mTOR activity.
AMPK/AKT Switch Hypothesis
  • Resistance training activates the AKT pathway, leading to mTORC1 activation and increased protein synthesis.
    • 4E BP1 inhibits 4IF4E, resulting in a net increase in protein synthesis and muscle hypertrophy.
  • Endurance training activates the AMPK pathway.
    • AMPK can facilitate TSC1 and 2 (TORC signaling 1 and 2), inhibiting mTOR activity.
    • Blunts muscle protein synthesis.
Implications for Concurrent Training
  • Combining high amounts of endurance training with resistance training may be counterproductive due to the AMPK/AKT switch.

mTOR

  • Mechanistic Target of Rapamycin (formerly Mammalian Target of Rapamycin).
  • Regulates muscle protein synthesis via cell cycle progression, cell proliferation, and cell growth.
  • Stimulated by resistance training (with appropriate loads), insulin, and IGF-1.
  • Muscle glycogen and leucine availability are crucial for mTOR activation.
  • Downregulated by high AMP to ATP ratios.

AMPK

  • Activated Protein Kinase: Energy-sensing protein kinase.
  • Sensitive to changes in the cellular ATP to AMP ratio.
  • Increases glucose uptake, decreases glycogen synthesis, increases long-chain fatty acid oxidation.
  • Decreases mTOR activity and protein synthesis, increases mitochondrial biogenesis.
  • Elevated during glycogen depletion, high-volume work, and endurance exercise.
  • Excessively high volume loads increase AMPK activity, which is detrimental to resistance training adaptations.

Resistance Training and Signaling Pathways

  • Resistance training increases activity of P13K, PKB, mTOR, S6-4E BP1 pathways, modulating protein synthesis rates and muscle growth.
  • Increased AMPK activity decreases mTOR signaling, suppressing resistance training-induced muscle protein synthesis.
    • Activates the EF2K pathway, inhibiting muscle protein synthesis.
  • Sustained contractions (endurance activities) result in increased calcium flux, inhibiting protein synthesis.

Stimulation Frequency

  • Low-frequency stimulation (endurance) increases AMP, decreases glycogen, stimulates the AMPK pathway, inhibits mTOR.
  • High-intensity, short bursts (resistance training) stimulate IGF-1, P13K, and mTOR, positively impacting muscle protein synthesis.

mTORC1 and mTORC2 Overview

  • mTORC1: Responds to amino acids, stress, oxygen, energy, and growth factors; acutely sensitive to rapamycin.
    • Promotes cell growth by inducing anabolic processes and inhibiting catabolic processes.
    • Drives cell cycle progression.
  • mTORC2: Responds to growth factors, regulates cell survival and metabolism, and the cytoskeleton.
  • mTORC1 is positively stimulated by oxygen, amino acid availability, high energy levels, and growth factors, and it is inhibited by rapamycin and stress. mTORC1 then stimulates macromolecule biosynthesis, cell cycle progression, growth and metabolism, and it inhibits autophagy.
  • mTORC2 facilitates metabolism, cytoskeletal organisation and cell survival.
Components and Characteristics
  • mTORC1:
    • Serine threonine kinase
    • Raptor (scaffold protein)
    • PRAS40 (inhibitor)
    • Deptor (inhibitor)
    • MLST8 (unknown functions)
    • TTi1 and TL2 (scaffold proteins).
  • mTORC2:
    • Serine threonine kinase
    • RIG2 (scaffold protein)
    • MSin1 (scaffold protein)
    • Deptor (inhibitor)
    • MLST8, TTi1 and TL2 (as described previously)

Tissue-Specific Effects of mTOR

  • Hypothalamus: Regulates food intake (decreased in normal state, increased in obesity).
  • Adipose Tissue: Controls fat mass and glucose uptake (increased fat mass, decreased glucose uptake in obesity).
  • Muscle: Increases protein synthesis, decreases protein catabolism, improves muscle mass, improves glycogen synthesis (decreased muscle mass and glycogen synthesis in diseased/obesity model).
  • Liver: Lipogenesis, ketogenesis, and gluconeogenesis (increased lipogenesis and gluconeogenesis in obesity).
  • Pancreas: Cell growth, proliferation, improved beta cell mass, insulin secretion (progression to type 2 diabetes in obesity).

Practical Considerations

  • Excessive resistance training volume inhibits mTOR.
  • Amino acid supplementation is a positive stimulator of mTOR.
  • IGF-1 positively impacts the P13K pathway, leading to phosphorylation of AKT and muscle protein synthesis.
Rest Intervals
  • Shorter rest intervals (1 minute) lead to greater AMPK stimulation.
  • Longer rest intervals (5 minutes) result in less AMPK stimulation and greater AKT signaling.

Module 7 Takeaways

  • Glycogen and amino acid availability significantly impact resistance training adaptations and cell signaling pathways.
  • New adaptations may occur at the level of the brain, motor neurons, and neuromuscular junction.
  • Satellite cells play a large role in muscle hypertrophy.
  • Muscle swelling can give a false indication of muscle hypertrophy in the initial stages of training; high amounts of muscle soreness are not beneficial.
  • Volume load is important for hypertrophy.
  • Key signaling pathways: AKT, mTOR, and AMPK.
    • AKT activates mTOR, promoting muscle protein synthesis.
    • AMPK activation inhibits mTOR and muscle protein synthesis.