FATIGUE

Key  Concepts  

• fatigue  is  a  complex  phenomenon  involving  interplay  between  central  and

peripheral,  and  psychological  and  physiological,  factors
• factors  in  fatigue  include  “central  fatigue”,  substrate  depletion,  metabolite
accumulation,  electrolyte  disturbances,  dehydration,  hyperthermia  and
muscle  microtrauma
• the  factors  that  limit  sprint  and  endurance  performance  differ  markedly,
resulting  in  the  adoption  of  different  training  and  performance
enhancement  strategies
• VO2  max  and  lactate  threshold  are  used  as  measures  of  endurance
performance  potential,  with  the  latter  perhaps  the  best  predictor

Fatigue  

Fatigue  can  be  defined  as  a  “reduction  in  the  force  generating  capacity”  or  “an  
inability  to  maintain  the  required  or  expected  force  output”.    The  latter  is  defined  
by  specific  task  failure,  whereas  the  former  is  defined  by  a  reduction  
“reductionin  inthe  
force and power generating capacity”
FATIGUE!
maximal  force  generating  capacity  prior  to  task  failure.
“inability to maintain the required or expected force o
power output”

D.  G.  Allen,  G.  D.  Lamb,  and  

D.G.HAllen
.  Westerblad.    Skeletal  
et al. Physiol. Rev. Muscle  
88: 287-332, 2008 Fatigue:  Cellular  
(with permission, American Physiological Society)
Mechanisms.    Physiol.  Rev.  January  2008  88:287-­‐332.  

Fatigue  is  a  complex  phenomenon  that  involves  the  interplay  between  central  
factors,  which  are  usually  defined  as  those  which  affect  the  central  nervous  
system,  and  those  peripheral  factors  which  have  a  direct  influence  on  skeletal  
muscle  force  and  power  generation  and  the  various  physiological  systems  that  
support  skeletal  muscle.  

There  are  complex  interactions  between  central  and  peripheral  factors  (see  
Fatigue:
figure  below)  –  feedback   Mind sOver
from  contracting   keletal  m Muscle?!
uscles  appears  to  influence  
the  central  motor  drive  to  those  muscles,  thereby  modifying  exercise  
“It has long been recognised that the main seat of fatigue
performance.    If  that  feedback   is  bexercise
after muscular locked,   there  
is the centralis  nervous
greater   central  drive  and  
system.
improved  exercise  performance  Mosso longiago nitially,  but  
stated that eventually  
"nervous fatigue ispthe
remature  fatigue  due  to  
local  limitations  within   preponderating phenomenon
the  contracting   and muscular
skeletal   fatigue is also
muscles.  
at bottom an exhaustion of the nervous system.” There
appear, however, to be two types of fatigue - one arising
entirely within the central nervous system; the other in
Fatigue  Study  Guide     themselves
which fatigue of the muscles The  Uis niversity  
superadded toof  Melbourne  - 2014  
that of the nervous system.”

F.A. Bainbridge, 1919

 Biochemistry (3rd Ed).
(with perm
Interactions of central and peripheral mechanisms!

T.D. Noakes et al. Brit. J. Sports Med. 1995 (with

permission, British Medical Journal Publishing Group)
Image  courtesy  of  Prof.  T.  Noakes  and  Dr.  A.  St.  Clair  Gibson.    University  of  Cape  
Town,  Sth.  Africa.  

Potential  factors  involved  in  central  nervous  system  fatigue  include  

• neuroglucopenia  (reduced  glucose  supply  to  brain)
• cerebral  hypoxemia
• hyperthermia
• pain
• amphetamines,  caffeine  –  modify  sensations  of  fatigue  
Glucose
• experiences,  emotions,   availability and central
motivation  
fatigue during exercise!
• existence  of  “central  governor”?  

Excitation-contraction coupling coupling,  as   and

In  terms  of  understanding  the  factors  contributing  to  fatigue  within  contracting  
skeletal  muscle,  review  the  basic  steps  in  excitation  contraction  
these  are  potential  sites  of  fatigue.    Some  of  the  mechanisms  causing  fatigue  here  
potential
are  summarized   in  the  figure  bfatigue
elow.   mechanisms! FIGURE 2—Knee extensor force (A) and voluntary activation per-
centage (B) during 2 min of sustained MVC performed after 15 min of
warm-up (baseline) and immediately after 3 h of cycling with or
without glucose supplementation. Maximal isometric contraction was
attempted by the subjects throughout the 2 min, and electrical stim-
ulation was superimposed every 30 s to assess the voluntary activation
of motoneurons. The external knee extensor force is presented in % of
preexercise MVC, and data are means ! SE for eight subjects.
* Significantly lower compared with glucose trial and baseline values
(P < 0.05).

cebo trial was associated with a significantly lower volun-

FIGURE 1—Blood lactate (A), blood glucose (B), and rating of per-
ceived exertion (C) during prolonged exercise with or without glucose tary activation percentage at 60, 90, and 120 s of contraction
L. Nybo. Med. Sci. Sports Exerc.compared
35: 589-594, 2003
with the other
supplementation. Data are means ! SE for eight subjects. * Signifi- two conditions, whereas the level
cantly different from the trial with glucose supplementation (P < 0.05).
(with permission, Lippincott,Williams
of central & Wilkins)
activation was similar in the glucose trial as
compared with the baseline situation (Fig. 2B). Total muscle
force (MVC#EL) did not differ between the placebo and
whereas it only reached a value of 13 ! 1 in the euglycemic glucose trial (Table 1), and EL nerve stimulation of the
trial (Fig. 1C). relaxed muscle applied 15 s after termination of the sus-
During the sustained MVC, the average force production tained MVC elicited a similar force in the placebo trial (102
was reduced from 222 ! 20 N in the glucose trial to 197 ! ! 8 N) as compared to the glucose trial (98 ! 10 N).
21 N in the placebo trial (P " 0.05), and both postexercise
values were significantly lower than the baseline value of
DISCUSSION
248 ! 23 N. Of note, the force was similar at the onset of
the maximal contraction in the placebo and glucose trials, The present results demonstrate that in endurance-trained
and the lower average force production in the placebo trial subjects 2—Knee
FIGURE the development
extensor forceof(A)hypoglycemia during pro-
and voluntary activation per-
was mainly the result of an impaired voluntary force pro- longed(B)
centage exercise
during 2was
minassociated
of sustained with
MVCan impaired
performed neuromus-
after 15 min of
FIGURE 2—Knee(baseline)
warm-up extensorand
force (A) and voluntary
immediately after 3 hactivation
of cyclingper-
with the
or
duction during the last half of the sustained MVC (Fig. 2A). cular
centage without
(B) performance
during 2 min of during MVC
sustained a sustained
performed contraction,
after 15 minand
of
glucose supplementation. Maximal isometric contraction was
The reduced voluntary force development during the pla- warm-up lower force
(baseline)
attempted production
by and
the immediately
subjects seemed
after to
throughout 3 h
the be somewhat
2 of cycling
min, related
with to
or stim-
and electrical
without ulation
glucosewas
supplementation. Maximal
superimposed every 30 s toisometric
assess thecontraction was
voluntary activation
CNS FATIGUE AND PROLONGED EXERCISE attempted by the subjects
of motoneurons. Medicine
Thethroughout& Science
theextensor
external knee 2 min,in Sports is&presented
Exercise
and electrical
force stim- 591
!in % of
ulation was superimposed
preexercise MVC, every 30 s to
and data areassess
means the !voluntary
SE for activation
eight subjects.
of motoneurons. The external
* Significantly knee extensor
lower compared force istrial
with glucose presented in % ofvalues
and baseline
preexercise MVC,
(P < 0.05). and data are means ! SE for eight subjects.
* Significantly lower compared with glucose trial and baseline values
(P < 0.05).

FIGURE 1—Blood lactate (A), blood glucose (B), and rating of per-
ceived exertion (C) during prolonged exercise with or without glucosecebo trial
 
cebo trial was associated with a significantly lower volun-
tary activation percentage at 60, 90, and 120 s of contraction
was associated with a significantly lower volun-
supplementation.
FIGURE 1—Blood Datablood
lactate (A), are means ! (B),
glucose SE for
andeight subjects.
rating of per-* Signifi- compared with the other two conditions, whereas the level
cantly(C)
ceived exertion different
duringfrom the trialexercise
prolonged with glucose
with supplementation (P < 0.05).tary activation
or without glucose percentage at 60, 90, and 120 s of contraction
of central activation was similar in the glucose trial as
D.  G.  Allen,  G.  D.G. Allen
D.  Lamb,   and  etH.  al. Physiol. Rev.
Westerblad.   88:
 Skeletal   M287-332,
uscle  Fatigue:  
compared
2008Cellular  
with the
withother two conditions, whereas
2B).the level
supplementation. Data are means ! SE for eight subjects. * Signifi-
cantly different from the trial with glucose supplementation (P < 0.05). compared the baseline situation (Fig. Total muscle
of central activation was similar in the glucose trial as
force (MVC#EL) did not differ between the placebo and
Mechanisms.  (with  Physiol.  
whereas R itev.  
permission, January  
only reached
trial (Fig. 1C).
2
a value of 13 008  
! 1 in the8 8:287-­‐332.  
American Physiological
compared
euglycemic with trial
glucose
force (MVC#EL)
relaxed muscle notSociety)
the baseline situation
(Table 1),
didapplied
(Fig.
and EL
differ
2B).stimulation
nerve
15 sbetween
Total muscle
the placebo
after termination
of the
of and
the sus-
whereas it only reached
During a value of
the sustained 13 !the
MVC, 1 in the euglycemic
average force productionglucosetained
trial MVC
(Table 1), and
elicited EL nerve
a similar force stimulation
in the placebooftrial
the(102
trial (Fig.was
1C).reduced from 222 ! 20 N in the glucose trial to 197 !relaxed!muscle 8 N) asapplied
compared 15 tos the
afterglucose
termination of !the10sus-
trial (98 N).
During21 theNsustained MVC, the average force production
in the placebo trial (P " 0.05), and both postexercise tained MVC elicited a similar force in the placebo trial (102
was reduced from
values were ! 20 N in the
222significantly glucose
lower to 197 !value of! 8 N) as compared to the glucose trial (98 ! 10 N).
trialbaseline
than the
21 N in the " the DISCUSSION
248placebo
! 23 N.trial
Of (P
note, 0.05), andwas
force both postexercise
similar at the onset of

Fatigue  Study  Guide     The  University  of  Melbourne  -  2014  

values were significantly
the maximal lower than
contraction in thetheplacebo
baseline andvalue of trials,
glucose The present results demonstrate that in endurance-trained
DISCUSSION
248 ! 23and N. the
Of lower
note, the forceforce
average was production
similar at the onset
in the of trial
placebo subjects the development of hypoglycemia during pro-
the maximalwas contraction in theofplacebo
mainly the result and glucose
an impaired voluntarytrials,
force pro- The longed
presentexercise
results demonstrate
was associated that in endurance-trained
with an impaired neuromus-
and the lower
ductionaverage
duringforce production
the last half of theinsustained
the placeboMVCtrial
(Fig. 2A).subjects theperformance
cular development of hypoglycemia
during during pro-
a sustained contraction, and the
was mainly Thethereduced
result voluntary force development
of an impaired voluntary force during
pro-the pla-longedlower force
exercise wasproduction
associatedseemed
with antoimpaired
be somewhat related to
neuromus-
duction during the last half of the sustained MVC (Fig. 2A). cular performance during a sustained contraction, and the
CNS FATIGUE AND PROLONGED EXERCISE Medicine & Science in Sports & Exercise 591
The reduced voluntary force development during the pla- lower force production seemed to be somewhat related! to
 (with permission, Wiley)

Much  attention  has  focused  on  potential  metabolic  factors  in  fatigue  –  these  
involve  substrate  depletion  and/or  metabolite  accumulation,  both  of  which  
impact  on  the  rate  of  ATP  turnover.    It  is  interesting  to  speculate  on  whether  the  
decline  in  force  is  due  to  reduced  ATP  turnover,  or  whether  the  rate  of  ATP  
turnover  is  rMuscle ATP
educed  to  a  level   turnover
entirely   appropriate   andfor  afatigue:
 force  output  that  is  
lower  due  to  some  other  fatiguing  mechanism?  
cause or effect?!

L.L. Spriet
L.  L.  Spriet,  K.  Soderlund,   etergstrom,  
M.  B al. J. Appl. Physiol.
and  E62:
.  H611-615, 1987
ultman.    Anaerobic  energy  
(with permission, American Physiological Society)
release  in  skeletal  muscle  during  electrical  stimulation  in  men.    J.  Appl.  Physiol.
February  1,  1987  62:611-­‐615.  

Strategies  to  enhance  fatigue  resistance  include:  

• training  –  physical,  technical,  mental
• nutrition  –  CHO,  fluid,  protein?
• heat  acclimatization,  cooling
• supplements,  drugs?  gene  doping?

Sprinting  Performance  

Determinants  of  sprinting  performance  include:  

• muscle  mass  to  generate  force  and  power
• fast  twitch  fibres
• neuromuscular  recruitment
• fast  reaction  time
• ability  to  generate  and  tolerate  acidosis  (buffer  capacity)

Factors  contributing  to  fatigue  during  high  intensity,  sprinting  exercise  include:  
• hyperkalemia  –  increased  ECF  K+  due  to  release  from  contracting  skeletal
muscle  
• CP  depletion  –  dietary  creatine  supplementation  is  associated  with
increased  CP  availability  and  improved  sprint  performance  
• muscle  glycogen  depletion  unlikely,  although  there  may  be  loss  of
glycogen  locally  at  key  sites  of  ATP  utilization  eg.  SR?  
• acidosis  (increased  [H+])  –  some  debate  on  direct  effects  of  H+  on  cross-­‐
bridge  cycling  and  force  production,  but  does  appear  to  reduce  ability  to  
maintain  force  output  which  implies  and  effect  on  ATP  turnover;  induced  

Fatigue  Study  Guide   The  University  of  Melbourne  - 2014  

 alkalosis  (increased  ECF  pH)  and  increased  muscle  buffer  capacity  due  
either  to  sprint  training  or  dietary  β–alanine  supplementation  (which
ENDURANCE PERFORMANCE!
increases  muscle  carnosine,  a  buffering  molecule  in  muscle)  are  
associated  with  enhanced  sprint  exercise  performance  
High VO2 max (>70ml.kg-1.min-1)
Adaptations  to  sprint  training  include:  
Ability
• increased   muscle  toNamaintain high %VO2 max
+/K+  ATPase  and  improved  K+  regulation

• increased  muscle  buffer  capacity  

( fractional utilisation )
• enhanced  muscle  lactate/H+  transport  capacity
Cadel Evans by Michael Jelijs (CC BY 2
www.flickr.com/photos/56658705@N
• increased  glycolytic  enzymes  
High power output at lactate threshold (LT)
• increased  VO2  max  and  muscle  oxidative  capacity  
– muscle
• no  good  evidence   oxidative
of  significant   capacity
changes   in  muscle  fibre  type  distribution

Fatigue resistance
Endurance  Performance  
Efficient/economical technique
Determinants  of  endurance  exercise  performance  include:  
Ability
• high   to oxidise fat at high power outputs
VO2  max  
• ability  to  maintain  a  high  %VO2  max  (“fractional  utilization”)  during
exercise
• high  power  output  at  lactate  threshold  (LT)  –  related  to  muscle  oxidative
capacity
• ability  to  oxidise  power  at  high  power  outputs
• efficient/economical  technique

VO2  max  sets  the  upper  limit  for  aerobic  energy  production  during  exercise,  
whilst  muscle  oxidative  capacity  is  associated  with  the  lactate  threshold,  
fractional  utilization  and  the  ability  to  maintain  power  output  during  prolonged  
VO2 max, muscle QO2 and endurance!
exercise  performance.  

K.J.A. Davies et al. Am. J. Physiol. 242: E418-E427, 1982

K.  J.  Davies,  J.  J.  Maguire,  
(with G .  A.  Brooks,  
permission, P.  R.  DPhysiological
American allman,  and  Society)
L.  Packer.    Muscle  
mitochondrial  bioenergetics,  oxygen  supply,  and  work  capacity  during  dietary  
iron  deficiency  and  repletion.    Am.  J.  Physiol.  Endocrinol.  Metab.  June  1,  1982  
242:E418-­‐E427.  

Fatigue  Study  Guide   The  University  of  Melbourne  -  2014  

The  figure  above  summarises  results  from  an  experiment  in  which  laboratory  
rats  were  made  severely  iron  deficient  through  dietary  iron  restriction.    This  
reduces  red  cell  mass  and  [Hb]  and  muscle  oxidative  capacity.    Iron  was  restored  
to  the  diet  and  rats  recovered  over  the  next  week.    As  you  can  see,  VO2  max  
increased  in  line  with  the  recovery  in  haematocrit  (%red  cells  in  blood),  
consistent  with  the  notion  that  oxygen  delivery  is  the  primary  determinant  of  
VO2  max.    Running  endurance  on  the  other  hand,  was  restored  in  parallel  with  
the  recovery  in  muscle  oxidative  capacity  (as  measured  by  muscle  pyruvate  
oxidase).  

There  is  a  high  correlation  between  muscle  oxidative  capacity  and  the  lactate  
threshold  (LT).    For  this  reason,  the  measurement  of  blood  lactate  levels  during  
submaximal  exercise,  including  LT  determination,  is  commonly  used  in  the  
routine  assessment  of  endurance  athletes.    There  is  strong,  positive  correlation  
between  exercise  time  to  fatigue  and  LT.    This  association  may  be  partly  related  
to  the  inverse  relationship  between  muscle  glycogen  use  during  exercise  and  LT.  

Potential  factors  in  fatigue  during  endurance  exercise  include:  

• “central  fatigue”
• hyperkalemia  and  loss  of  muscle  potassium  (although  the  increase  is
smaller  in  magnitude  with  each  contraction,  over  time  the  cumulative
effect  can  be  significant)
• reduced  SR  Ca2+  release  –  lower  ATP  and  glycogen  close  to  the  SR  may
affect  Ca2+  release  and  uptake  by  and  from  the  SR
• muscle  glycogen  depletion
• hypoglycemia  which  results  in  reduced  muscle  CHO  oxidation  and
neuroglucopenia
• dehydration  –  impaired  cardiovascular  and  metabolic  function
• hyperthermia

Carbohydrate  and  fluid  ingestion  enhance  endurance  exercise  performance  via  

mechanisms  that  appear  to  be  independent  and  additive.  

Adaptations  to  endurance  exercise  training  with  implications  for  performance:  

• increased  VO2  max  –  increased  maximal  stroke  volume  an  cardiac  output
• expanded  blood  volume
• increased  muscle  capillary  density
• increased  muscle  oxidative  capacity
• increased  muscle  Na+/K+  ATPase  and  improved  K+  regulation
• reduced  reliance  on  muscle  glycogen  and  blood  glucose  and  the  same
energy  expenditure;  increased  fat  oxidation
• possible  increase  in  type  I  fibres?

If  you  wish  to  read  more  on  the  physiology  of  endurance  exercise  performance,  
the  following  article  may  be  of  interest:  
Joyner,  M.J.  and  E.F.  Coyle.    Endurance  exercise  performance:  the  physiology  of  
champions.    J.  Physiol.  586:  35-­‐44,  2008.  
http://jp.physoc.org/content/586/1/35.long  

Fatigue  Study  Guide   The  University  of  Melbourne  - 2014  

Reading  

Hargreaves,  M.    Metabolic  factors  in  fatigue.    Gatorade  Sports  Science  Institute  
SSE#98.  
http://www.gssiweb.org/Article/sse-­‐98-­‐metabolic-­‐factors-­‐in-­‐fatigue  

Hargreaves,  M.    Fatigue  mechanisms  determining  exercise  performance:  

integrative  physiology  is  systems  biology.    J.  Appl.  Physiol.  104:  1541-­‐1542,  
2008.  
http://jap.physiology.org/content/104/5/1541.long  

Noakes,  T.D.    In  sport  is  it  all  mind  over  matter?    Dialogues  in  Cardiovascular  
Medicine.  17:  46-­‐55,  2012.  
http://www.dialogues-­‐cvm.com/past-­‐issues/2012_17_1/63_05/  

Discussion  Topic  

The  great  Finnish  distance  runner  Paavo  Nurmi  once  said  “Mind  is  everything,  
muscles  pieces  of  rubber.    All  that  I  am,  I  am  because  of  my  mind”.    Is  fatigue  
simply  a  case  of  “mind  over  muscle”?  

Abbreviations  

A arterial
ADP adenosine diphosphate
AP action potential
ATP adenosine triphosphate
CHO carbohydrate
CON control/placebo trial
CP/PCr creatine phosphate/phosphocreatine
ECF extracellular fluid
FV femoral vein
GLY glycogen
Hb haemoglobin
HR heart rate
LT lactate threshold
Pi inorganic phosphate
QO2 muscle oxidative capacity
ROS reactive oxygen species
RyR ryanodine receptor or SR Ca2+ release channel
SM skeletal muscle
SR sarcoplasmic reticulum
TT transverse tubule
VO2 oxygen uptake
VO2 max maximal oxygen uptake

Fatigue  Study  Guide   The  University  of  Melbourne  -  2014