1 Principles of Skeletal Muscle Adaptation Brooks ch 19 p

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

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5 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 Myoplasticity

6 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 Myoplasticity

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9 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.

10 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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13 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 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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16 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

17 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 Signals for Adaptation

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21 GH stimulates liver release of IGF 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 Signals for Adaptation

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23 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 Signals for Adaptation

24 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. Signals for Adaptation

25 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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28 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

29 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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31 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

32 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

33 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 Types Percent Slow Twitch Fibers Twin B Twin A Twin B Twin A Identical TwinsFraternal Twins

35 Elite athletes - specialized fiber typing –sprinters II b, endurance athletes type I –Fig 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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41 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

42 Table 19-1 Succinate DH (Krebs) –response varies with fiber type - involvement in training –inc max blood flow, capillary density, and potential for O 2 extraction Endurance Adaptations

43 - Increases in oxidative enzyme mRNA several hours after endurance exercise - no change in cytoskeletal factors (Titin)

44 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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46 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 Adaptations to Resistance Training

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48 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 % dec in mito protein Adaptations to Resistance Training

49 Fig cap density dec 13% Adaptations to Resistance Training

50 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 –VO 2 max dec 25 % –Strength improvement lost completely Adaptations –reduction in ms and ms fiber X-sec area - decrease in metabolic proteins –Fig Inactivity / detraining

51 Adaptations –reduction in ms and ms fiber X-sec area - decrease in metabolic proteins –Fig Inactivity / detraining