Transcript Principles of Skeletal Muscle Adaptation

Principles of Skeletal Muscle
Adaptation
Brooks ch 19 p 430- 443
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Outline
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Myoplasticity
Protein turnover
Proposed regulatory signals for adaptation
Fiber Type
Training
Inactivity
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Myoplasticity
• Altered gene expression - results in an increase or decrease in
the amount of specific proteins
– tremendous potential to alter expression in skeletal muscle
– The adaptations result in more effective aerobic or resistance exercise
– This is the molecular basis for training adaptations
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Myoplasticity
• Chemical messengers have an important role in stimulating
adaptations to exercise training
– Chemical messengers respond to physical and mechanical stress,
neural signals, metabolic, bioenergetic, hypoxic and temperature
signals resulting from aerobic or resistance exercise
• 20% of skeletal muscle is protein, balance is water, ions...
– All proteins can be regulated by altering gene expression
• Fig 19-2 cascade of regulatory events impacting gene
expression
– Muscle gene expression is affected by changes induced by
loading state and the hormonal responses occurring with
exercise
– Regulation occurs at any level from transcription to post
translation
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– transcription factors interact with their response elements
to
affect promotion of various genes
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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 Transcription
Factors (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)- increased 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 extra-cellular space
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Signals for Adaptation
• Insufficient energy intake
– Leads to protein degradation for fuel
• anorexia, sarcopenia
• Increased cortisol
– inhibits protein synthesis by blocking AA uptake into muscle, blocks GH,
IGF-1 and insulin actions
– Stimulates protein degredation
- 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
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• May utilize myogenic regulatory factors to stimulate transcription
Signals for Adaptation
• 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 and incorporation of satellite cells
• Muscle release of IGF-1 independent of ciculatory IGF-1 release
induced by GH
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Signals for Adaptation
• GH stimulates liver release of IGF-1 8-30 hours post exercise
• muscle release of IGF-1 induced by RE
• more important for muscle specific adaptations
– Fig 19-4
• Exerts Autocrine/paracrine effects
• MGH - mechanogrowth factor
– Training inc IGF-1 mRNA expression
• Inc GH dependant /independent release
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Signals for Adaptation
• Endurance Training
– small rise during exercise
• Greater rise when training above lactate inflection point
– GH – positive correlation between GH and aerobic
fitness
– GH may be mediator of increased O2 and substrate
delivery and lipid utilization by exercising muscle
• Improves FFA oxidation - stimulating lipolysis during but mainly
after exercise
• Reduces glucose uptake after exercise by inhibiting insulin action
– GH may also play a role in improved thermoregulation,
conversion of muscle fibers to more oxidative and upregulation of oxidative genes to improve mitochondrial
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function that occur with endurance training
Signals for Adaptation
• Resistance Training (RE)
– Testosterone and GH - two primary hormones that may
affect adaptations to RE
– Both Inc secretion with training
– Testosterone - inc GH release
• Inc muscle force production - Nervous system influence
• Direct role in hypertrophy still being investigated
– IGF-1, T and RE required to stimulate satellite cells and
result in hypertroyphy and increased strength.
– Muscle damage from RE also stimulates satellite cell
proliferation.
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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)
– Calcium - Calmodulin Dependant protein kinase
– Unknown whether calcium plays an essential role in hypertrophy
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Metabolic Regulation
• Redox state of cell is influenced by activity level.
– The content of Reactive oxygen species (ROS) increases with
duration of activity (endurance)
• ROS along with hypoxia and low cellular engergy activate a
cascade of transcription factors stimulating growth of
mitochondria
– increase aerobic enzyme content (more study required)
– May have influence in conjunction with Thyroid hormone on mitochondrial
DNA – up-regulating mitochondrial biogenesis and beta oxidation
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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 needs to increase
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Acute Exercise and Glucose metabolism
• 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 to surface
• AMPK - regulated by intracellular ratios of ATP:AMP and
CP:creatine
– Acute AMPK- stimulates migration of GLUT 4 to surface
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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 an 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 with Ca++ or AMPK
– Increased GLUT 4 protein content
• increases capacity for glucose uptake from circulation
– may improve glucose tolerance during early stages of the
development type 2 diabetes by stimulating insulin sensitivity or 32
increasing GLUT 4 migration
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
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helping elucidate control pathways
Hereditability of Fiber Types
0
0
0
Fraternal Twins
Twin A
60
40
20
80
Identical Twins
Twin A
60
40
20
80
Percent Slow Twitch Fibers
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40
Twin B
60
80
0
20
40
Twin B
60
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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
• 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
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Endurance Adaptations
• 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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- Increases in
oxidative enzyme
mRNA
several hours after
endurance exercise
- no change in
cytoskeletal factors
(Titin)
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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)
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Adaptations to Resistance Training
• 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
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Adaptations to Resistance Training
• 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
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Adaptations to Resistance Training
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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Inactivity / detraining
• Adaptations
– reduction in ms and ms fiber X-sec area - decrease in
metabolic proteins
– Fig 19-10
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