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Skeletal muscle plasticity frommolecules to training protocols
Carlo ReggianiUniversity of Padova
Flexibility
The same muscles used for differenttasks thanks to neural control (m.u.recruitment and discharge pattern)
Plasticity
Skeletal muscles change theirstructure and function to bettercope with their tasks
Plasticity is regulation of muscle fibre type, size (and possibly number )
Plasticity is regulation of muscle fibre type, size (and possibly number )
Adaptative change of muscle fibre size
atrophy
hypertrophy
Disuse/inactivity
Fasting
Cachexia
Cytochines
Myostatin
Load/resistance training
IGF-1
Androgens
Resistance training
load
Nervous system learning
Improved MU recruitment and MN discharge
Muscle fibre hypertrophy
Resistance training
load
Nervous system learning
Improved MU recruitment and MN discharge
Muscle fibre hypertrophy
Load sensors
Signallingpathways
↑Protein synthesis
↓Protein degradation
Load sensors: transducers of tension into chemical signals
Costameric proteins: integrins - FAK
Sarcomeric proteins: titin – titin kinase
Signalling pathways for hypertrophy
Three models of hypertrophy induced without load:
�IGF 1 overexpression
�AKT overexpression
�Myostatin knock out
v
Spontaneous mutations resulting in muscle hypertrophy
Myostatin mutation in cattle
Myostatin mutation in humans
AKT power !Hypertrophy induced in muscle fibres * transfected in
vivo with a plasmid over-expressing AKT
*
*
*
**
*
*
*
IGF-1 and AKT pathways are linked together
plasma membrane
SR
myofibrils
cytosol,mitochondria
nucleus
AKT
IGF-1
IGF-1 receptor +
PI3 K
AKT
FOXO- P
FOXO
Atrogin (MAFbx)
4E-BP1
eIF-4E
Proteinsynthesis in ribosomes
mTOR
S6K
S6
Proteindegradation in proteasome
AKT increases protein synthesis at ribosomes and inhibits ubiquitinizationand protein degradation
Inducible AKT overexpression
No increase in proportion of new myonuclei generated duringhypertrophy development
Only protein accumulation or also myonucleiaddition to achieve hypertrophy ?
Only protein accumulation or also myonucleiaddition to achieve hypertrophy ?
8 weeks resistance training – upper limbs, young subjects (19-29 y)
pre post 0
500
1000
1500
myo
nucl
ei /
mm
3
16 weeks knee extension resistance training
Only protein accumulation or also myonucleiaddition to achieve hypertrophy ?
Plasticity is regulation of muscle fibre type, size (and possibly number)
Myosin isoforms as markers of fibre type
Myosin isoforms can be identified with ATPase staining, antibodies, gel electrophoresis, PCR
Myosin is the molecular motor of muscle contraction
Myosin isoforms are associated with distinct values of speed of contraction, power output, ATP consumption rate
Fibre types in skeletal muscle
Slowfibres
Fastfibres
2A
2X
2B
Contractionspeed
Resistance tofatigue Metabolism
low
high low
oxidative
glycolytic
high
In human muscles only 1, 2A and 2X fibres
Effects of motor neuron silencing in human skeletal muscle
normal
spinal cordinjury
slow myosin fast myosin
J. Andersen – S. Schiaffino
Activity and innervation are necessary for slow fibre expression in regenerating muscles
Inn Den
Stainingfor slow myosin(soleus)
When denervated, regenerating muscles becomehomogeneously fast
myc-cain MyHC-slow
*
* *
*
If calcineurin is blocked by expression of the peptide inhibitor cain/cabin-1,the expression of MyHC-slow is blocked in regenerating rat soleus
plasma membrane
SR
myofibrils
Gene transcription
cytosol,mitochondria
nucleus
Searching for transcription factors involved in excitation-transcription coupling: calcium released from SR can control transcription ?
calcineurin
NFAT
fiber type
calmodulin
calcium
Calcineurin
P
NFAT
P
Kinases
Cytoplasm Nucleus
TranscriptionNFAT NFAT
NFAT
Tibialis anterior
Fused tetanus at 150 Hz and unfused tetanus at 20 Hz
Only repeated trains at 20 Hz (slow stimulation pattern) induces NFAT nuclear translocation
Nuclear translocation of NFATc1-GFP induced by 20Hz (slow-like) but not 150Hz (fast-like) stimulation
20Hz 150Hz
conclusion
• Muscle plasticity is highly specific• Depending on load and activation pattern
distinct intracellular pathways are activated
• This leads to the required changes in muscle fibre size and type
acknowledgments
• VIMM – Padova– Stefano Schiaffino
– Marco Sandri– Bert Blaauw
• Dept of Anatomy and Physiology (University of Padova)– Luana Toniolo
– Marta Canato
Supported by
MYOAGE – VII EU framework
MIUR – Italian Ministry of University and Research
ASI – Italian Space Agency