Principles of Skeletal Muscle Adaptation

1. Principles of Skeletal Muscle Adaptation • Brooks ch 19 p 401-420 • Outline • Myoplasticity • Protein turnover • Proposed regulatory signals for adaptation • Fiber Type • Training • Inactivity • Injury

2. Myoplasticity • Altered gene expression - resulting in an increase or decrease in the amount of specific proteins • tremendous potential to alter expression in skeletal muscle • This is the molecular basis for adaptations that occur due to exercise • 20% of sk ms is protein, balance is water, ions... • All types of protein can be regulated by altering gene expression • Fig 19-1 cascade of regulatory events - impacting gene expression • Often modifies activity of transcription factors or hormone response elements • Cascade of interactions between factors • Eg c-fos, c-jun, CREB, MAPK

3. Myoplasticity cont. • myoplasticity - change either quantity (amount) or quality (type) of protein expressed • Eg. Responses to training • type IIb - hypertrophy (enlargement) - inc amount of protein in fiber • larger fast II b fiber • Another fiber - hypertrophy • also repress gene for fast II b myosin HC, turn on fast IIa myosin HC • not only enlarged, but change in contractile phenotype • larger, slower contracting fiber.

4. Protein turnover • Protein Turnover reflects 1/2 life of protein - time frame for existence • protein transcribed (DNA-mRNA) • translated then degraded • level of protein in cell 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 that are 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 19-2 - many factors can modify microenvironment of fiberwhich in turnregulates 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 • 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 training above lactate inflection • Resistance Training • Testosterone and GH - two primary hormones that affect adaptations • Both Inc secretion with training • Testosterone - augments GH release • Inc muscle force production - Nervous system influence

8. Metabolic Regulation • Many proposed factors related to onset of 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) • Unkown 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 mitochondria • 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 • Through 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 increase • 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 ATP:AMP and CP:creatine • Acute AMPK- increases GLUT 4 migration

10. Chronic exercise and Glucose metabolism • Chronic increases in Ca++ maystimulate 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 sensitivty 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 - knowledge of molecular biology is helping elucidate pathways of control.

12. Muscle Fiber Types • Elite athletes - specialized fiber typing • sprinters II b, endurance athletes type I • Fig 19-3 - 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 17-28b - 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 19-4 (5-6 month longitudinal study) • II - 33% , 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 19-5 - 25 % dec in mito protein • Fig 19-6 - 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 19-8

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