Skeletal muscle adapts to exercise training specific to the training stimulus
Muscle contractions result in transient increases in mRNA which typically return to baseline in ~24 hours.
So . . . maintaining increased mRNA levels requires frequent bouts of exercise to produce and maintain protein synthesis.
What initiates these “molecular cascades” that result in training adaptations in skeletal muscle???
“Putative Primary Messengers” in cell signaling
Mechanical stretch
“Mechanical perturbation” of skeletal muscle _______ calcineurin, mitogen activated protein kinase (MAPK), and insulin-like growth factor (IGF, IGF-1) signaling cascades.
The _____and _____ of contractions result in the activation of different signals and may underlie the specific adaptations to different modes of training.
Endurance training, especially, has been shown to result in improved Ca2+ cycling and _______.
Mitochondrial Redox Potential
During exercise, maintenance of the redox potential (NAD-/NADH) is accomplished by the oxidation of __ in the mitochondria.
This mitochondrial activity results in increased levels of ________.
Increased levels of ROS appear to trigger adaptations by increasing the binding of DNA transcription factors such as ___________ and _______
ROS may also stimulate adaptations by acute changes in mitochondrial metabolism and myofilament _____.
Muscle Phosphorylation Potential
[ATP]/[ADP][Pi] is the _ potential
Energy charge of the cell:
([ATP] + (1/2 [ADP]))/([ATP] + [ADP] + [AMP] + [Pi])
Increased levels of or decreased ____regulate energy pathways (i.e., glycolysis) An increased AMP/ATP ratio ________ AMP kinase (AMPK) an important secondary messenger
SECONDARY MESSENGERS
AMPK
Most studies looking at AMPK used exercise; few studies with __ training
Acute activation of AMPK results in increased non-insulin dependent __________
AMPK also promotes utilization
Chronic effects of AMPK include gene expression enhancing FFA oxidation and decreased _______
Studies suggest that as fitness level increases, greater stimulus/intensity may be required to activate AMPK. For example, one study of trained men (some endurance, some strength) showed AMPK activation when they switched _____.
Currently, the AMPK pathway is thought to be more associated with adaptations to training rather than training.
Ca2+ – calmodulin – dependent kinase (CaMK)/calcineurin signaling
detect and respond to calcium.
CaMK II & IV are associated with activation of gene expression of and _ proteins, respectively.
CaMK II activity has been shown to with wheel running (mice and rats) and cycling exercise in humans.
This increase in activity appears to occur in an _ –dependent manner.
CaMK activation may exert its effects via nuclear factor of activated T-cells (NFAT) and _____________________ signaling
Calcineurin appears to stimulate muscle hypertrophy in conjunction with IGF but also seems to promote gene expression favoring __ metabolism.
These pathways seem counterproductive but the specific responses may depend on specific _.
Insulin-like growth factor (IGF) Pathway
IGF signaling pathway plays a role in muscle hypertrophy and _____ metabolism
Contractile activity stimulates IGF-1 which exerts its effects via _ ((hypertrophy) and (glucose transport)
Conflicting results of studies examining Akt role in muscle adaptation to training may be result of
1) ___________________
2) _________________
3) _________________
The ___ pathway plays a key role in regulation of muscle hypertrophy via both stimulatory and inhibitory pathway.
Mammalian target of rapamycin (mTOR)
mTOR signaling pathways produce many different _.
Two common pathways involve mTOR – G-BL protein complex and either rapamycin sensitive _ or protein.
mTOR rictor appears to activate _______ regulation (eukaryotic initiation factor)
The actin cytoskeleton participates in many fundamental processes including the regulation of cell , _, and ___.
The remodeling of the actin cytoskeleton is dependent on ______ proteins, which organize actin filaments into specific structures that allow them to perform various specialized functions.
mTOR raptor promotes cell growth via __, eIF4E binding protein (4E-BP1) and eIF4B
mTOR raptor suppresses _ which decreases its inhibition of eIF4E
Strength training (especially eccentric contractions) – but NOT endurance training – activates .
_ training has been shown to decrease 4E-BP1 inhibition of eIF4E. ___ training seems to do the opposite.
Cytokine signaling
Cytokines are polypeptides released in the _____ response to exercise-induced muscle damage.
Tumor Necrosis Factor-TNF-) inhibits IGF-mediated protein synthesis and promotes insulin _.
TNF- binding to cell membrane results in activation of a kinase (IB) that inhibits _______________.
When IB is phosphorylated, NFB is free to initiate gene expression promoting protein degradation. Studies suggest this pathway “exacerbates” _ in skeletal muscle.
Aerobic exercise at a relatively low intensity may __ TNF-.
High intensity ______________training may acutely increase TNF- but may lower it long-term.
Several studies have shown that both aerobic and resistance training may reduce inflammation (TNF-) and protein degradation (NFB ) and reduce _________ in response to exercise.
More specifically, acute bouts of exercise activate NFB early in training while long-term training may down-regulate NFB, promoting __.
Endurance training results in
• _ glycogen stores
• Improved insulin and glucose metabolism
• _ FFA oxidation
• Improved lactate kinetics
• Type I muscle fiber hypertrophy
• Transition of Type _ fibers to Type _
• Increased mitochondrial density
• Increased capillary density
Endurance training can increase mitochondrial protein content 50 – 100% but a rapid turnover requires a _ training stimulus.
Mitochondrial Biogenesis
Mitochondrial biogenesis is a complex process that requires transcription factors and co-factors such as ________________ and ______________.
EGR-1 promotes transcription of ___________________.
NRF 1 & 2 appear to exert control of ______________________.
All of these increase in response to ___ training.
PGC-1has been proposed as a “_________” of mitochondrial biogenesis.
In response to endurance exercise, PGC-1promotes
• Mitochondrial protein
• Tfam activation via
PGC-1is co-activator of _______________________.
Three PPAR subtypes regulate lipid homeostasis by increasing gene expression promoting __________.
___ training does not appear to influence PGC-1or PPAR.
Metabolic Gene Expression
Endurance training induces up-regulation of metabolic genes encoding enzymes or transporters such as hexokinase, lipoprotein lipase and ___________________________.
Resistance training may produce similar changes but primarily in _______ metabolism.
Muscle hypertrophy in response to resistance training results from increased protein synthesis which results from increased ___________.
and binding protein appear to be prime candidates in mediating the increased mRNA translation in response to strength training.
IGF-1 mediated protein synthesis involves the _________________signaling pathway
• S6K and 4E-BP1 phosphorylation
• eIF4E-eIF4G association
Activation of this pathway results in increased gene expression, ribosomal translation, and _______ activation
_ contractions in particular have been shown to induce muscle damage.
This damage appears to activate satellite cells via the myogenic regulatory factor (MRF) family of transcription factors such as ________ and _______ transcription factors.
MRFs may also play additional (and unknown) roles in the adaptations to ________________training.
Concurrent Training
Studies are ___ on the outcomes of simultaneous aerobic and resistance training.
“Interference” phenomenon may be the result of molecular _______.
Elongation phase of translation (and muscle protein synthesis) is mediated by ________.
eEF2 is inactivated by phosphorylation by eEF2K in response increased energy demand or decreased ____ typically associated with aerobic exercise.
Activation of eEF2K is regulated “upstream” by calmodulin & MPK pathways activated by _ exercise.
On the other hand, _ pathways appear to inhibit eEF2K and activate eEF2.
Phosphorylation of eEF2K by both S6K and mTOR in response to resistance training activates eEF2 and promotes_______________________.
Forkhead box O1 (FoxO1) transcription factor promotes mitochondrial biogenesis and ____ breakdown.
Both activity and abundance of FoxO1 is regulated by Akt __.
The AMPK-Akt pathways comprise a proposed “_________”.
Prolonged low-frequency stimulation of muscle fibers (imitating __ training) produced increased AMPK-TSC2 activity, PGC-1gene expression and inhibition of mTOR-mediated translation.
High frequency stimulation (mimicking __ training) produced increased Akt-mediated hypertrophy, decreased AMPK, and suppression of TSC2 activity.