Principles of Skeletal Muscle Adaptation

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Principles of Skeletal Muscle Adaptation

Brooks ch 19 p 430- 443

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• Myoplasticity• Protein turnover• Proposed regulatory signals for adaptation• Fiber Type• Training• Inactivity

Outline

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• 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

MyoplasticityMyoplasticity

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• 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– transcription factors interact with their response elements to affect

promotion of various genes

MyoplasticityMyoplasticity

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• 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

Myoplasticity cont.

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• 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

Protein turnover

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• 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

Adaptation

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• 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• May utilize myogenic regulatory factors to stimulate transcription

Signals for Adaptation

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• 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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• 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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• 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 up-regulation of oxidative genes to improve mitochondrial function that occur with endurance training


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• 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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• 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

Metabolic Regulation

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• 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

Metabolic Regulation

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• 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

Acute Exercise and Glucose metabolism

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• 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

Acute Exercise and Glucose metabolism

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• 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 increasing GLUT 4 migration

Chronic exercise and Glucose metabolism

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• 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

Phenotype

Hereditability of Fiber TypesPercent Slow Twitch Fibers

Twin B

Twin

A

0 20 40 60 80

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Twin B

Twin

A

0 20 40 60 80

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60

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0Identical Twins Fraternal Twins

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• 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

Muscle Fiber Types

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• 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

Endurance Adaptations

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• 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

Endurance Adaptations

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- Increases in oxidative enzyme mRNA several hours after endurance exercise

- no change in cytoskeletal factors (Titin)

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• 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)

Adaptations to Resistance Training

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• 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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• 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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Fig 19-8 - cap density dec 13%


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• 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

Inactivity / detraining

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• Adaptations– reduction in ms and ms fiber X-sec area - decrease in

metabolic proteins– Fig 19-10

Inactivity / detraining

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Principles of Skeletal Muscle Adaptation