Sarcopenia Flashcards
LO
1. understand how skeletal muscle changes with ageing and impact on frailty in older ppl
2. know the multi-factorial drivers and molecular pathways responsible
3. understand the rationale for therapeutic management of sarcopenia
What is sarcopenia?
The loss of skeletal muscle mass and strength that comes with advancing age
What starts to happen from age of 25 years?
loss of skeletal muscle mass
Visible on MRI x-ray scans, reduced CSA of lean mass and increase in adipose tissue
What happens to muscle strength with ageing? and what also is affected…
muscle isometric strength declines with age
muscle power also declines
Muscle ageing is not just losing muscle mass
decline in muscle power with age tends to be X than decline in muscle mass
greater
muscle isometric strength declines with age and is proportional to what?
the decline in muscle mass
ageing causes an increase in adipose tissue which has a profound effect on metabolism, true or false?
true
what stays fairly constant while muscle and fat in muscle changes with age?
water content
What 3 diagnostic tools are available to look at skeletal muscle mass decline via measurement of CSA of mid thigh?
DXA - Dual energy X-ray absorptiometry
MRI
CT scan
What 4 diagnostic tools are used to measure function and strength decline?
Grip strength
Timed up and go (TUG) test
Gait speed
Physical performance battery (steps up+down stairs)
What is the difference between the mitochondria of healthy young muscle and older muscle?
young muscle has lots of mitochondria
older has fewer and they are less efficient
What effect does reduced mitochondria in older muscle have on the functional aerobic capacity of muscle (muscle quality)?
reduces it
..
.regardless of losing muscle mass
How do mitochondria generate energy for muscle contraction?
oxidation of fuels
Give 3 things that skeletal muscle provides?
strength, posture and movement
skeletal msucle also regulates what rate?
metabolism/ metabolic
Give one process that skeletal muscle is THE major organ for?
insulin stimulated blood glucose uptake from tissues 80%
effect of losing muscle mass on glucose in body?
more glucose stays in bloodstream, not pulled out.
as skeletal muscle: major organ for insulin-mediated blood gluc uptake!
List some consequences of sarcopenia to elderly patients?
- Reduced strength
- Loss of physical function + independence
- Increase risk of falls
- Reduced capacity to withstand chemo
- prolonged hospitalisation
Obesity leads to the accumulation of triglycerides in skeletal muscle.
What effect does this have on insulin stimulated glucose uptake? and what condition can this lead to?
inhibits and diabetes
what has a big effect in metabolic function of muscle?
fat adipose tissue surrounding muscle + intracellular fat
normal response to insulin levels increase form pacreas after a meal?
insulin binds insulin receptor + signal transduction occurs. glucose from blood –> skeletal muscle
after a meal… glucose from blood –> skeletal muscle can only occur if what?
if GLUT4 can translocate to muscle cell membrane + there transporter can pull glucose form blood -> muscle cells
how does fatty acid build up form becoming overweight impact insulin signalling pathway?
(how doe sthis lead to diabetes?)
insulin binds to receptor but inhibits downstream signalling of it… no translocation/ GLUT4 to cell memb thus –> diabetes as cant pull glucose out of bloodstream anymore
T2DM insulin sensitivity with age
what increases risk of developing T2DM esp with age?
loss of muscle mass and gain of fat mass
There is an increased or reduced expression of GLUT4 with age and obesity in skeletal muscle tissue?
reduced
Which isolated myotubes are intrinsically insulin resistant?
obese
what effect does BMI and central adiposity have on the risk of developing type 2 diabetes?
increases
WHR > 0.8 effect of risk of T2DM?
apple shaped
higher risk
Outline how sarcopenia leads to fraility? 2 mechanisms, p 167
↓ strength/ power + proprioception -> ↓ mobility, ↑ fall + fracture risk
↓ muscle mass + ↑ fat -> ↑ insulin resistance
all-> frailty
what are muscle fibres defined by?
the type of myosin heavy chain expressed
Are slow or fast twitch muscles fatigue resistant?
slow (type I)
What are features of type I muscle fibres?
- speed
- metabolism type
- express what myosin/s
Slow twitch fibres - fatigue resistant
Oxidative metabolism
Express myosin heavy chain type I (MHC-I)
What are features of type IIB and IIX fibres?
- speed
- metabolism type
- express what myosin/s
Fast twitch fibres
Glycolytic metabolism
Express MHC-IIB or MHCIIX myosin
type IIB and IIX fibres generate what force and for what time periods?
Generation of maximal force for short periods
What are features of type IIA fibres?
- speed
- metabolism type
- express what myosin/s
Fast twitch
Oxidative metabolism
Express MHC-IIA myosin
fast twitch fibres? (3)
and how do these differ?
IIB and IIX (glycolytic metabn)
IIA (oxidative metabn)
the 2 types of fibres that observe oxidative metabolism
I
IIA
Do most postural muscles contain mostly slow type I fibres or fast type II fibres?
slow type I
what type of fibres needed for quick burst of energy eg getting up out of chair?
type II (2)
Are slow or fast twitch muscles fatigue resistant?
slow
Which type of muscles are composed mostly of type I slow twitch fibres?
slow twitch muscles
What type of muscle is composed by mostly composed of type II fast fibres (IIb and IIA) which fatigue quickly ?
fast twitch muscles
marathon runners have muscles with higher relative % of what type of fibres?
slow twitch fibres
Type 1 fatigue resistant
sprinters have muscles with higher relative % of what type of fibres?
fast twitch
Type 2 fatigue quickly
give one condition which may exhibit skeletal muscles with pronounced type II fast fibre atrophy?
osteoarthritis
i.e. the type 2 fast fibres: smaller in size in OA px muscles
how do the fibre types switch in px with COPD?
higher proportion but smaller size of of type IIX (fast) fibres
normal things that increase muscle mass.. and decrease it?
exercise: gain muscle mass
sit around: lose it
as muscle expects to be stimulated
What are some of functional consequences of motor unit remodelling with age (denervation of type II fast fibres. atrophy)?
less precise control,
loss of balance + speed, reduced maximal force generation
effect of aging on innervation of neurones and what does this ->?
motor unit remodelling and lose innervation…. (as motor neurones connected to muscle fibres by nerves)
–> muscle fibre atrophy
in sarcopenia, why do you lose a lot of type 2 fibres?
nevres that connect motor neurones to fibres been degraded + muscle thinks its no longer needed as not being stimulated.
atrophies in response
skeletal muscle is a very plastic tissue and is constantly remodelling. How often is there a complete renewal of muscle mass?
3-4 months
skeletal muscle mass contantly remodelling, why must it be controlled?
as need balance between atrophy and growth
Skeletal muscle (myofibrillar) mass is maintained by the balance between what two things?
skeletal muscle protein synthesis
skeletal muscle protein degredation
Is the activity of muscle anabolic signalling pathways for protein synthesis or degredation?
synthesis
is the activity of catabolic signalling pathways for skeletal muscle synthesis or degredation?
degradation
Skeletal muscle (myofibrillar) mass balance is affected how, in sarcopenia? scales tipped
LESS protein synthesis
MORE protein degradation
What is the proteasome system in skeletal muscle?
(p175, dont need lot of details)
A type of catabolic signalling pathways
- Ub activated by ubiquitin-activating enzyme E1
- Activated Ub -> ubiquitin conjugating enzyme E2
- E3 ligases attach E2-Ub complex to protein substrates to be degraded
- Repeated conjugation of Ub mols generates a polyubiquitin chain serving as degradation signal for 26S proteasome
- protein substrate degraded, free Ub recycled
proteasome system role is essentially what
and what does it target?
degrades proteins -> amino acids.. wants to target specific (tagged) proteins
tag = Ub first binds E1 then E2 then E3 ligand. critical
ligates Ub complex -> protien being degraded. protein substrate
get chain of Ub acts as tag to send target + be recognised by p system
= comples of proteins will recognise chain of Ub as sign for protein to be degraded
degrades it + releases Ub back to circn + protein fragments
most important step in proteasome system?
E3 ligation step
ligation Ub enz complex -> proteins to be degraded
what regulates the atrophic signal in muscle? …2
(only expressed in skeletal muscle, not other tissue types)
muscle specific E3 ligases (atrogenes)
MAFbx (Atrogene-1) and MurF1
how does HYPERtrophic signal -> ↓ protein degradation in catabolic signalling pathways?
p177
mTOR/AKT activated
FOXO (TF) phosphorylated
no translocation of FOXO
no atrogene induction
…↓ protein degradation
how does Atrophic signal -> ↑protein degradation in catabolic signalling pathways?
p177
mTOR/AKT DEactivated
FOXO (TF) DE-phosphorylated = translocation of FOXO
induction of atrogene expression
…↑ protein degradation
use of:
hypertrophic signal
atrophic signal
building muscle mass
opposite: no exercise, sit around
why does atrophic signal -> dec protein synth?
inc protein degradation?
due to deactivated mTOR.
FOXO can enter nuc and turn on E3 ligase expression
why does hypertrophic signal ->
inc protein synth?
dec protein degradation?
mTOR activated, protein synth turned ON
E3 ligase expression in nuc BLOCKED
hypertrophic and atrophic signal acc both work together to regulate what?
amount of degradtaion in muscle (and synth?)
What is the role of AKT or mTOR?
Promotes muscle protein synthesis +inhibits muscle proteolysis via inhibition of FoxO
What is AKT/ mTOR activated by? 3
pic p178
By IGF-1/insulin, growth hormones (inc testosterone) + resistance exercise
what drug class inactivates mTOR/AKT?
glucocorticoids…. and thus dec protein synthesis
myostatin: -ve regulator of ?
muscle mass
What does myostatin bind to for induction of atrogenes?
activin receptor type iib
- binding to ActRIIB inhibits AKT/mOR
- activates FOXO leading to atrogenes induction
What do high levels of myostatin mean?
Drives degradation - more loss of muscle
myostatin/TGF-beta pathwya:
inhibition of myostatin produces what?
muscle hypertrophy (growth)
What are the factors that drive sarcopenia?
- Age-related ↓ in anabolic hormones eg testosterone + growth hormone
- Anabolic blunting
- ↓ physical activity or immobilisation/disuse
- ↑ in inflammatory cytokines due to changes in immune function with ageing - inflammaging
- Nutrition - protein deficiency
- Neuromuscular changes + motor neuron remodelling
What is meant by anabolic resistance/ anabolic blunting?
loss of muscle mass with aging in part due to intrinsic change in response of muscle to amino acids and not food uptake alone
old vs yound: comparison of IV admin essential amino acids to stimulate muscle protein synth?
fail to stimluate to same degree vs younger
true even for high doses
How many weeks of disuse is sufficient to lose significant muscle mass, strength and power?
2
What does disuse of muscle lead to?
significant loss of muscle mass, strength and power
Inactivity activates muscle catabolic pathways, true or false?
true
What happens to the expression of atrogenes during 2 weeks of immobilisation?
increase of expression
- MAFb
- MuRF1
Increase in muscle catabolic pathways, with no muscle use… inc protein degradation
MAFbx and MuRF1 must be rapidly regulated after exercise started , why?
genes turned off as soon as exercise started.
rapidly regulate to regulate muscle mass
effect of immobility on muscle mass? eg elderly/ hospital bedbound
dec
a major contributor to sarcopenia is…
inflammation
esp inflamm chronic disease
sarcopenia accelerates in inflammatory chronic disease, true or false?
true
How does inflammation contribute to sarcopenia?
there will be more sarcopenia if more inflammation caused by chornic disease like renal failure, HF, COPD, RA,
or
acute, rapid wasting disorders: sepsis, AIDS, end-stage cancer cachexia - would be faster sarcopenia due to more inflammation
sarcopenia made worse with what? 3
inactivity
anabolic resistance
inflammation
What are pro-inflammatory cytokines that inc w ageing + obesity?
TNF alpha
IL-1 beta
IL-6
whats an inflamm cytokine that increases in RA, ageing, OA, obesity?
TNFa
What is the effect of pro-inflammatory cytokines in sarcopenia?
They promote atrophy of myotubes
What is the role of MuRF-1 and MAFbx and when do they increase?
These are E3 ligases that promote/regulate skeletal muscle atrophy
- these increase with inflammation which drives muscle mass
also induction is caused by TNFa stimulation of myotubes
what effect does being conditioned in obese adipose conditioned media have on myoblasts (muscle cells)?
develop into thinner myotubes (muscle fibres)
older muscless is X resilient to inflamm. changes
less
myoblasts cultured in presence of adipokine resistin exhibit impaired myogenesis. What effect does this have on the myotubes that develop? 2
reduced thickness and reduced nuclear fusion index
older muscle cells thickness and ability to fuse is both…
decreased
Give one inflammatory condition which would lead to sarcopenia?
chronic liver disease
does CLD induce or inhibit myotube atrophy?
induce
What are effects of chronic liver disease that can lead to sarcopenia? ()
p189
- inflammation –> increased MAFbx and MURF1
- reduced nutrient intake
- increased starvation
- malabsorption
- less metabolic substrates -> less glycogen
- more amino acids broken down for energy
- increased serum ammonia and reduced ammonia clearance
- increased myostatin (inhibits myostatin)
INDUCES MYOTUBE ATROPHY
whats the top upregulated gene (CLD px)
and effect on protein synth?
DEPTOR, an mTOR inhibitor.
mTOR drives protein synth
thus this SUPPRESSES PROTEIN SYNTH
What are some of the factors that drive muscle atrophy in cancer patients (cachexia)?
- drug therapy
- reduced food intake
- reduced activity
- age (sarcopenia)
- elevated levels of pro-inflammatory cytokines !!
There are no approved pharmacological therapeutics for sarcopenia but there are 2 drug classes that may be beneficial to patients. What are these?
androgen receptor modulators (Testosterone)
beta 2 agonists (clenbuterol)
Androgen receptor activators are used to promote?
muscle protein synthesis.
Androgen receptor activators (testosterone) downside?
CV side effects and testicular atrophy
= not recommended for men
How do beta 2 agonists help patients with sarcopenia?
induce calpastatin expression which regulates muscle mass by inducing growth
What are 2 CV side effects of using beta 2 agonists such as clenbuterol for the treatment of sarcopenia?
tachycardia and blood pressure
Myostatin inhibitors (myostatin monoclonal antibodies) are in development and are efficacious in murine models with humanised anitbody showing tolerability in phase I. What is an alternative strategy being developed to this?
soluble myostatin decoy receptor (ActRIIB-Fc)
Name 4 multifactoral driving factors for sarcopenia?
inactivity, obesity, nutrition and illness
how do myostatin inhibitors promote muscle mass + strength?
by Inhibiting mysostatin
