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Summary Fatigue, Aging & Disuse
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Fatigue, aging and disuse – SummarySevere muscle wasting in aging and many chronic diseases > decreased mobility
> higher risk of fractures. Adaptation of muscle fiber size is always the net effect
of protein synthesis and degradation (protein turnover). Only the size of the fibers
changes but not the number of the fibers.
Protein synthesis
Muscle fibers can be up to 10cm in length and are multinucleated. Fibroblasts
produce collagen (myofibroblasts). Myonuclei under the sarcolemma.
Transcription > translation > post-translational modification
mRNA is complementary to non-coding strand to be the same as the coding
strand. RNA has Urine instead of Thymine and Ribose
instead of Deoxyribose. rRNA from the nucleolus
forms ribosomal subunits, tRNA transfers amino acids
towards the ribosomal subunits. Introns are spliced,
exons are the coding regions. Introns can be spliced in
different ways (alternative splicing). 5’-end is modified
by the addition of a cap, 3’-end gets a poly-A-tail.
Translation can be divided in different steps:
activation > initiation > elongation > termination.
Translation from 5’-end to 3’-end. Activation: tRNA is
loaded with a specific amino acid by specific aminoacyl-tRNA synthetase.
Initiation: Transcription Factors (TF’s), RNA polymerase and mediators bind to
the promoter region. Enhancer sites can be thousands of base pairs up- or
downstream but may be physically close. TF’s can be either activators or
suppressors > regulation by phosphorylation or dephosphorylation.
Elongation: amino acids (amino group, side chain, hydrogen, carboxyl group)
are coupled in the ribosomes. Start codon is always for Methionine (AUG), 3 stop
codons.
Termination: No tRNA can recognize the stop codons but releasing factors can
and cause release of the polypeptide chain.
Post-translational modification includes folding of the protein, cleavage, adding or
releasing side chains.
Exercise induced initiation: eIF4 denatures the 7mG cap at the 5’ end so that the
43S complex of the ribosome can bind the mRNA and scan along for the start
codon. When the start codon has been found eIF2 and 5 are displaced and the
80S ribosome is formed. eEF1 & eEF2 are regulators of elongation. eEF2 opens
the ribosomal complex and translocate it 3 bases down the mRNA to the next
codon. eRF’s regulate termination by directing tRNA with anti-codons for the
stop codon. Half-life time of mRNA is also a regulating factor.
Translation can also be regulated by tissue-specific expression of miRNA’s.
miRNA’s complementary to mRNA cause degradation or block the translation.
Example: myostatin normally inhibiting muscle cell proliferation can be blocked
by miRNA’s extreme muscle growth/hypertrophy.
,Humans do express myosin type
IIb genes but a mutation in the
promoter region prevents
translation.
, Protein degradation
4 systems/ways of protein degradation:
1. Calpain/Caspase
2. Lysosomes
3. Ubiquitin proteasome
4. Oxidative stress (ROS)
Calpains and caspases are Ca2+ activated cytosolic proteases, concentrated at
the Z-disk of the sarcomers > Degradation of cytoskeletal proteins. Relatively
high [Ca2+] is required to activate calpains (5-4000 µM). Expression is increased
by unloading. Caspases are involved in apoptosis (local apoptosis in muscle
cells>apoptotic myonuclei).
Lysosomes break down organelles by endocytosis. Low pH in vesicles that work
for enzymes like proteases. Degradation of
membrane proteins.
The proteasome degrades proteins that have
been tagged by Ubiquitin. E1&E2 pick up
Ubiquitin from the cytosol, E3 ligase connects
Ubiquitin to protein. E3 ligase works tissue
specific and largely determines which proteins
will be degraded. MuRF1 and MAFbx are E3
family members working in the muscle.
ROS damages membranes and DNA. The main
source of production are the mitochondria
though, even when you are inactive. Xanthine oxidase / vitamin C can prevent
the damage by accepting the extra electron free radicals carry. ROS are not only
the ‘bad guys’; NO is crucial for hypertrophy (mechanism?).
Interplay of degradation systems: ROS > release of cytochrome C from
mitochondrial membrane > caspase cascade > caspase 3 is cleaved > damages
DNA & induction of apoptosis > breakdown of cytoskeleton > ubiquination.
VO2max of a single muscle cell is related to SDH absorbance. When
hypertrophying you lose aerobic capacity. To increase mitochondrial density >
enhanced blood supply/myoglobin is required.
Muscle plasticity
Satellite cells are on top of the muscle fiber (between sarcolemma and basal
membrane) > muscle stem cells. Stem cell properties: quiescent, myogenic
potential, ability to self-renew.
Pax-7 is a TF expressed by satellite cells, used for fluorescent staining. In muscle
wasting a decline in the number of and impaired function of satellite cells.
Functions of satellite cells
1. Maturational muscle growth > higher expression of proteins by nuclei.
Satellite cell number on fibers decreases during growth, correlated with
increase in myonuclei thus indicating differentiation.
2. Muscle hypertrophy > myonuclear domain remains constant by increase
of the number of myonuclei. In experiments where myonuclear domain
increased (by depletion of satellite cells) the quality was preserved. Not
clear to what extent satellite cells are necessary for hypertrophy.
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