Muscle Fatigue biom2012 Lecture 2 PDF

Muscle fatigue biom2012 (Lecture 2) Prof Bradley Launikonis [email protected] Types of muscle fatigue: a) High frequency fatigue - fast onset - fast recovery b) ‘Metabolic’ fatigue c) Long duration fatigue Stages of metabolic fatigue in an intact muscle...

Muscle fatigue biom2012 (Lecture 2) Prof Bradley Launikonis [email protected] Types of muscle fatigue: a) High frequency fatigue - fast onset - fast recovery b) ‘Metabolic’ fatigue c) Long duration fatigue Stages of metabolic fatigue in an intact muscle fibre. A B D Force C Caffeine D B Caffeine A C Modified from Westerblad & Allen, 1991.  extracellular space sarcolemma intracellular space Contractile proteins Less force due to less Ca2+ release and/or decrease in force development by contractile proteins. Ca2+ DHPR Ca2+ Ca2+ Voltage Ca2+ sensitive sarcoplasmic reticulum (SR) Ca2+ molecules Ca2+ Ca2+ Ca2+ Ca2+ What ‘metabolites’ cause metabolic fatigue? Q. What is the energy source for muscle? A. Adenosine triphosphate (ATP) Sites of ATP usage extracellular space sarcolemma intracellular space ATP ATP T-tubule Contractile proteins ATP ATP Ca2+ pump Ca2+ DHPR Ca2+ Ca2+ Voltage Ca2+ sensitive sarcoplasmic reticulum (SR) Ca2+ molecules Ca2+ Ca2+ sarcoplasmic reticulum (SR) Ca2+ Ca2+ RyR Ca2+ release channels ATP utilization ATP2- binds Mg2+ = MgATP Adenosine triphosphate (ATP) Adenosine- P P P Adenosine diphosphate (ADP) Adenosine- P P + Pi Adenosine monophosphate (AMP) Adenosine- P + Pi + Pi MYOADENYLATE DEAMINASE Inosine 5´-monophosphate (IMP) ADENOSINE Short term ATP → ADP + Phosphate (~50 mM) Cr-Phosphate + ADP → ATP + Cr Longer term ATP is also remade: From glucose and oxygen in mitochondria (‘Aerobic’) GLUCOSE + 6 O2 + ADP + 36 Pi  36 ATP From glucose alone (‘Anaerobic’) GLUCOSE + 2 ADP + 2 Pi  2 ATP + 2 LACTATE + 2 H+ Metabolic changes inside of the fibre extracellular space sarcolemma intracellular space Light exercise: Phosphate  Intense exercise (anaerobic):  Phosphate, lactate, H+, Mg2+ ADP, AMP  ATP, pH, glycogen, Cr Ca2+ Ca2+ Ca2+ Ca2+ sarcoplasmic reticulum (SR) Ca2+ Ca2+ Ca2+ Ca2+ Ca2+  Metabolic changes inside of the fibre extracellular space sarcolemma intracellular space Contractile proteins Ca2+ DHPR Ca2+ Ca2+ Voltage Ca2+ sensitive Pi + Ca2+ Ca-Pi Ca2+ molecules Ca2+ Ca2+ sarcoplasmic reticulum (SR) Ca2+ Ca2+ RyR Ca2+ release channels = sites that could cause fatigue T- tubule Myoplasm SR Inhib. Kd ~0.1mM 2+ Mg ATP DHPR Stimulatory site Ca 2+ 2+ Mg Act. Kd ~1M RyR1 Skeletal T- tubule Myoplasm SR ADP,  AMP Inhib. Mg2+ Kd ~0.1mM 2+ ATP Mg ATP DHPR Stimulatory site 2+ Ca Mg 2+  Ca2+ as Act. Kd ~1M Ca-P forms RyR1 Skeletal Summary of metabolic changes and effects ↑Pi and Mg2+ decrease contractile function.  Pi reduces the free [Ca2+] in the SR (eg. CaP forms).  H+ (ie.  pH) has little effect on overall ECC.  ADP and AMP compete with ATP for the stimulatory site on RyR, thus reducing RyR opening and Ca2+ release.  Mg2+ makes it harder for the DHPR to open RyR.  ATP (to low levels) decreases RyR opening Doesn’t Lactic acid cause fatigue? How come he hasn’t talked about it yet? Lactate myth began in 1929. Just because there is a correlation or a relationship between fatigue and lactic acid doesn’t mean it is the cause of the fatigue File:Archibald Vivian Hill.jpg A.V. Hill -Lactate stimulates glucose production in the liver (tissue-to-tissue signaling) -Readily diffusible fuel which is used by the heart and brain (lactate breaks down further to form pyruvate) -Lactate is involved in the release of human growth hormone Additionally, In McArdle’s disease, patients fatigue at a far quicker rate yet they lack glycogen phosphorylate meaning they can’t produce lactate during glycolysis.  No lactate 3mM Cl- lactate Zero Cl- longer slower From glucose alone (‘Anaerobic’) GLUCOSE + 2 ADP + 2 Pi  2 ATP + 2 LACTATE + 2 H+ Acidosis decreases the permeability of Cl- channels, so... the normal ratio of PK : PNa : PCl is 1 : 0.01 : 2 -88 mV Was changed to PK : PNa : PCl is 1 : 0.01 : 1 -88.4 mV or PK : PNa : PCl is 1 : 0.01 : 0 -89.3 mV Types of muscle fatigue: a) High frequency fatigue b) ‘Metabolic’ fatigue c) Long duration fatigue (lasts days!) -caused by stretching the muscle while contracting (eccentric damage eg. Walking downhill)? Low frequency stimulation (ie 20 Hz) - Raising [Ca2+]intracellular too much or for too long. Muscle damage with ‘Eccentric contraction’ Stretching muscles while contracting (eg. walking downhill) Ca2+ and Stretch-induced damage. flat downhill Ordered, uniform array  Electron micrographs of normal muscle sarcomeres Takekura et al (2001) J. Physiol. 533, 571  After eccentric contractions Takekura et al (2001) J. Physiol. 533, 571 Disruption  Elevated Ca2+ causes damage extracellular space sarcolemma intracellular space Contractile proteins Ca2+ damage to contractile proteins Ca2+ Ca2+ Ca2+ Ca2+ sarcoplasmic reticulum (SR) Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ High Ca2+ activated calpains (Ca2+ dependent protease) and severs the mechanical link between RyR and DHPR  Interference in any of the EC coupling processes fill cause fatigue. extracellular space sarcolemma intracellular space Contractile proteins Ca2+ DHPR Ca2+ Ca2+ Voltage Ca2+ sensitive sarcoplasmic reticulum (SR) Ca2+ molecules Ca2+ Ca2+ Ca2+ Ca2+ = sites that could cause fatigue  Is Muscle fatigue bad: No ! Muscle fatigue is a normal process that prevents further more serious damage, which could lead to cell death. Therefore, fatigue is beneficial.  Practice short answer question: The development of muscle fatigue depends on the muscle fibre type. Briefly describe the roles and power output of the two major muscle fibre types in skeletal muscle and how one type can be more resistant to fatigue than the other.