Principles of Skeletal Muscle Adaptation

1
Principles of Skeletal Muscle Adaptation

• Brooks ch 19 p 430- 443
• Outline
• Myoplasticity
• Protein turnover
• Proposed regulatory signals for adaptation
• Fiber Type
• Training
• Inactivity
• Injury

2
Myoplasticity

• Altered gene expression - resulting in an inc or
  dec in the amount of specific proteins
• tremendous potential to alter expression in
  skeletal muscle
• This is the molecular basis for adaptations that
  occur with training
• 20 of sk ms is protein, balance is water,
  ions...
• All types of protein can be regulated by altering
  gene expression
• Fig 19-2 cascade of regulatory events impacting
  gene expression
• Muscle gene expression is affected by loading
  state and hormones
• Regulation occurs at any level from transcription
  to post translation
• transcription factors, which interact with their
  response elements to affect promotion

3
Myoplasticity cont.

• Fig 19.2 continued
• Hormones bind to nuclear receptors (HR) and
  interact with DNA at Hormone response elements
  (HRE) to affect transcription
• Activity (loading) changes levels of certain TF
  (c-fos, c-jun, CREB, MAPK)
• Activity also changes levels of circulating
  hormones
• myoplasticity - change either quantity (amount)
  or quality (type) of protein expressed
• Eg. Responses to training
• quantity
• hypertrophy (enlargement) - increase amount of
  protein in fiber
• quality
• repress gene for fast II b myosin HC, turn on
  fast IIa myosin HC

4
Protein turnover

• Protein Turnover reflects 1/2 life of protein -
  time frame for existence
• protein transcribed (DNA-mRNA)
• translated then degraded
• level of cell protein governed by
• Balance of synthesis / degradation
• precise regulation of content through control of
  transcription rate
• and/or breakdown rate
• Mechanism provides the capacity to regulate
  structural and functional properties of the
  muscle
• applies to proteins involved in
• Structure, contraction, and transport
• as well as enzymes involved in metabolism

5
Adaptation

• Sk ms adaptations are characterized by
  alterations in functional attributes of muscle
  fibers through
• Morphological, Biochemical and Molecular
  variables
• adaptations are readily reversible when stimulus
  is diminished or removed (inactivity)
• Fig 19-3 - many factors can modify
  microenvironment of fiber which in turn regulates
  gene pool expression
• changes can lead to altered rates of protein
  synthesis and degradation
• changing content or activity of proteins
• Microenvironment includes the intracellular
  milieu and immediate extracellular space

6
Signals for Adaptation

• Insufficient energy intake
• Leads to protein degradation for fuel
• anorexia, sarcopenia
• nutrition also influence hormones
• Insulin - anabolic
• power developed by motor unit
• Recruitment and load on fibers
• specific responses result from
• Reduced power, sustained power, or high power
  demands
• May utilize myogenic regulatory factors to
  stimulate transcription
• Hormones - independent of nutrition
• thyroid hormone - gene expression at all levels
  pre and post transcriptional and translational
• Eg myosin heavy chain, SR Ca pump
• Importance with training is unclear
• IGF-1 - insulin like growth factor 1
• mediates Growth Hormone effects
• Stimulates differentiation of satellite cells

7
Hormones(continued)

• GH stimulates release of IGF-1 - from liver - 8
  -30 hours post exercise
• also muscle release of IGF-1
• more important for ms specific adaptations
• Fig 19-4
• Exerts Autocrine/paracrine effects
• MGH - mechanogrowth factor
• Training inc IGF-1 mRNA expression
• Inc GH dependant /independent release
• Endurance Training
• GH - no change at rest
• small rise during exercise
• Greater rise when training above lactate
  inflection point
• Resistance Training
• Testosterone and GH - two primary hormones that
  affect adaptations
• Both Inc secretion with training
• Testosterone - inc GH release
• Inc muscle force production - Nervous system
  influence

8
Metabolic Regulation

• Many proposed factors related to fatigue and the
  intracellular environment
• Calcium concentration increases 100 fold with
  muscle stimulation
• Increase is recruitment dependant and motor unit
  specific -
• influence varies with frequency and duration of
  stimulation and cellular location of calcium
• Calcium influences transcription through kinase
  cascades and transcription factors
• stimulating muscle growth in response to high
  intensity activity (hypertrophy)
• Unknown whether calcium plays an essential role
  in hypertrophy
• Redox state of cell is influenced by activity
  level.
• The content of Reactive oxygen species (ROS)
  increases with duration of activity (endurance)
• These activate cascade of transcription factors
  stimulating growth of mitoch.
• inc aerobic enzyme content (more study required)

9
Acute Exercise and Glucose metabolism

• Insulin and muscle contraction stimulate an
  increase in glucose uptake into muscle
• via different intracellular pathways (fig 1)
• Glucose Transporters (GLUT 4) migrate to cell
  surface from intracellular pools
• facilitated diffusion of glucose into cell
• Type II diabetes may involve errors in insulin
  signaling or the downstream stimulation of GLUT 4
  migration
• With exercise, delivery, uptake and metabolism of
  glucose need to inc
• Muscle contraction increases Ca and AMPK
  (AMP-activated protein kinase)
• Ca may act through CAMK (calmodulin-dependant
  protein kinase) or calcineurin
• Acute Ca stimulates migration of GLUT 4
• AMPK - regulated by intracellular ratios of
  ATPAMP and CPcreatine
• Acute AMPK- increases GLUT 4 migration

10
Chronic exercise and Glucose metabolism

• Chronic increases in Ca may stimulate
  transcription factors
• MEF2A, MEF2D, NFAT
• Levels of GLUT 4 protein and mitochondrial
  enzymes observed to increase in laboratory
  studies
• AMPK - regulated by intracellular ratios of
  ATPAMP and CPcreatine
• Chronic exposure to AMPK analog (AICAR) results
  in increased GLUT 4 protein expression, HK
  activity in all muscle cells
• CS, MDH, SDH, and cytochrome c increased in fast
  twitch muscle only
• Endurance training produces similar results to
  those indicated above
• Increased GLUT 4 content increases glucose uptake
  from circulation
• may improve glucose tolerance during early stages
  of the development type 2 diabetes by stimulating
  insulin sensitivity or increasing GLUT 4 migration

11
Phenotype

• When protein structure of muscle is altered - the
  phenotype changes
• Phenotype is outwardly observable characteristics
  of muscle
• Slightly different versions of proteins can be
  made - isoforms
• This reflects underlying genes (genotype) and
  their potential regulation by many factors (eg
  exercise)
• altered phenotypes - affect chronic cellular
  environment and the response to acute
  environmental changes (training effects)
• eg. Receptors, integrating centers, signal
  translocation factors and effectors are modified
  in content or activity-
• signaling mechanisms are not fully understood -
  molecular biology is helping elucidate control
  pathways

12
Muscle Fiber Types

• Elite athletes - specialized fiber typing
• sprinters II b, endurance athletes type I
• Fig 19-5 - elite - specialized at the ends of the
  fiber type spectrum
• genetics - has a strong influence on fiber type
  composition
• Training studies - alter biochemical and
  histological properties - but not fiber type
  distinction
• Fiber typing is according to myosin heavy chain
  isoform
• evidence, however, that intermediate transitions
  can occur in MHC expression
• not detected with conventional analysis
  techniques

13
Endurance Adaptations

• Occurs with large increase in recruitment
  frequency and modest inc in load
• minimal impact on X-sec area
• significant metabolic adaptations
• Increased mitochondrial proteins
• HK inc, LDH (dec in cytosol, inc in mito)
• 2 fold inc in ox metabolism
• degree of adaptation depends on pre training
  status, intensity and duration
• Table 19-1 Succinate DH (Krebs)
• response varies with fiber type - involvement in
  training
• inc max blood flow, capillary density, and
  potential for O2 extraction

14
Adaptations to Resistance Training

• Inc recruitment frequency and load
• Hypertrophy - inc X-sec area
• Increase maximum force (strength)
• Fig 17-31b - Force velocity after tx
• move sub max load at higher velocity
• enhance power output (time factor)
• Fiber type specific adaptation
• inc X-sec area of both type I and II
• Fig 19-6 (5-6 month longitudinal study)
• Type II - 33 , Type I-27 increase
• Fastest MHCs repressed
• inc in expression of intermediate MHC isoforms -
  some Type II x shift to II a
• mito volume and cap density reduced
• Fig 19-7 - 25 dec in mito protein
• Fig 19-8 - cap density dec 13

15
Inactivity / detraining

• Aging, space flight, bed rest, immobilization
  from injury
• large reduction in recruitment frequency and /or
  load
• Significant reduction in metabolic and exercise
  capacity in 1-2 weeks
• Complete loss of training adaptations in a few
  months
• VO2 max dec 25
• Strength improvement lost completely
• Adaptations
• reduction in ms and ms fiber X-sec area -
  decrease in metabolic proteins
• Fig 19-10

16
Injury and Regeneration

• Induced by a variety of insults
• force is high relative to capacity
• trauma, ischemia, excessive stretch
• eccentric exercise, mild compression
• Denervation also stimulates regeneration
• Individuals with an active lifestyle
• have a population of continuously regenerating
  fibers
• Two phases of injury
• immediate - mechanical damage
• secondary - biochemical
• occurs over several days - calcium and free
  radicals involved in cell death
• Followed by regeneration
• Requires revascularization, phagocytosis,
  proliferation of precursor cells, re-innervation
  and recruitment and loading