Transcript Principles of Skeletal Muscle Adaptation

Principles of Skeletal
Muscle Adaptation
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Brooks ch 19 p 430- 443
Outline
Myoplasticity
Protein turnover
Proposed regulatory signals for
adaptation
Fiber Type
Training
Inactivity
Injury
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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
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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
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•
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
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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
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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
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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
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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)
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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 (calmodulindependant protein kinase) or calcineurin
– Acute Ca++ stimulates migration of GLUT 4
• AMPK - regulated by intracellular ratios of
ATP:AMP and CP:creatine
– Acute AMPK- increases GLUT 4 migration
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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
ATP:AMP and CP:creatine
– 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
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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
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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
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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
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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 MHC’s 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%
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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
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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
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