Principles of Skeletal Muscle Adaptation Brooks ch 19 p 430- 443 Outline Myoplasticity Protein turnover Proposed regulatory signals for adaptation Fiber Type Training Inactivity Injury

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

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

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

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

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

Hormones(continued) Endurance Training Resistance Training 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

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)

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 (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

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

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

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

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

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%

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

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