Genetic Factors and Mechanical Signalling Pathways in Muscle Hypertrophy

Mechanical stimuli can influence phospholipase D, leading to a phospholipase D dependent increase in phosphatidic acid.
Phosphatidic acid is being explored as a supplement, although its effectiveness is uncertain.
Nutrients and growth factors can impact mTOR via a wortmannin-independent mechanism.

mTOR regulates muscle protein synthesis, cell cycle progression, cell proliferation, and cell growth.
mTOR is stimulated by resistance training.
Excessive volumes of resistance training can decrease mTOR.
Appropriate volume loads upregulate mTOR activity, leading to increased protein synthesis.
mTOR is impacted by the hormones insulin and insulin-like growth factor 1 (IGF-1).
mTOR activity is dependent on the availability of muscle glycogen: increased availability leads to increased mTOR activity, while depletion leads to decreased mTOR activity.
Amino acids, especially leucine, can increase mTOR activity. Protein powder supplements contain leucine.
Low energy availability, indicated by a greater amount of AMP compared to ATP, can impact mTOR.

Resistance training activates the IGF pathway, phosphorylating the AKT pathway, which upregulates mTOR, leading to increased translational activity and protein synthesis.
Endurance activity leads to reductions in glycogen, increases in AMP (in case of low energy availability), signaling the phosphorylation or upregulation of the AMPK pathway.
AMPK phosphorylation phosphorylates TORC signaling 2, downregulating mTOR activity.
AMPK upregulation does have a role of K, it can then result in an increase in transcription resulting in mitochondrial biogenesis, increasing aerobic capacity.

Mechanical signalling can activate the AKT pathway and impact the actin cytoskeleton.
Mechanical signalling can activate the AKT pathway, leading to mTOR and S6K activation, resulting in protein synthesis and muscle growth.
Mechanical signalling can cause a release of insulin-like growth factor, which binds with its receptor, activating P13K and the AKT pathway to promote muscle protein synthesis and muscle growth.
High neural activation and calcium entry into the cell (during endurance-type repeated contractions) lead to calcium-dependent calmodulin activation.
Calcineurin is activated, leading to NFAT (nuclear factor of activated T cells) activation.
Target genes are activated, promoting slow phenotype expression.

Amino acids can enter the pathway and upregulate mTOR, leading to increased protein synthesis, ribosomal biogenesis, and muscle growth.

Test exercise: Squats
Concentric only group: 8 sets of 8 repetitions at 85% of one rep max (1RM)
Eccentric only group: 8 sets of 8 repetitions at 110% of 1RM (eccentric loading/force capacity is typically above 100% concentric 1RM)
Subjects: Young healthy adults (average weight of 70-71 kg, 1RM squat of approximately 140 kg)

Increased mRNA for IGF-1 was more pronounced after eccentric contractions compared to concentric contractions.
Increased androgen receptor mRNA was observed for both concentric and eccentric contractions.
Normal training involves both concentric and eccentric contractions.
Concentric only contractions may not induce the same responses as combined contractions.
Eccentric contractions alone are also not optimal.
A group using both concentric and eccentric contractions would have been a useful comparison.

Myonuclei are stained blue.
Anti-neural cell adhesion molecule (NCAM+) is used to detect stem cells (satellite cells).
NCAM+ cells are identified as nuclei localized to the membrane of a myofiber and stained brown.

Mean fiber area improved significantly for young women, young men, older women, and older men after a 16-week training period.
The largest effect was noted in young men (20-35 years old).

The greatest change in myonuclei per fiber was observed in young men, who also had the greatest increase in mean fiber area.

mRNA for IGF-1 improved for both young and old adults.
Mechanical growth factor (MGF) was significantly improved for younger adults as an acute response and after the 16-week period compared to older adults.

Responders showed an increase in mean fiber area (MFA), NCAM+ cells, and nuclei per fiber area.
Non-responders showed a significant increase in NCAM+ cells but not as much increase in muscle fiber area or nuclei per fiber.
Indicates satellite cells are present, but there may be difficulty in proliferation and differentiation.
Responders showed larger increases in insulin-like growth factor and distinct changes in mechano growth factor.

The total volume load was higher in the three-set group.
3-set group averaged 64 kg, 14 to 11 to 9 repetitions per set.
Volume loads for the sets were similar between the two groups.
Myofibrillar fractional synthesis rate increased after both training configurations (5 hours later in a fed state).
Increase probably slightly higher for the three set group.
At twenty nine hours, this still at an increased rate for the three set group compared to the group that only performed one set of exercises.
The EIF2BE pathway decreased for the 3-set group.
P90 RSK1 improved for both groups at 24 hours.
P70 S6K, was elevated for both groups five hours post session in a fed state.

Receptor binding and cellular signals: Cytokines and other growth factors are sensed and activate a network of signal transduction pathways.
Nuclear translocation or activation of transcription factors: Active nuclear transcription factors, along with androgens and glucocorticoids, change the expression of major muscle growth regulators (IGF-1, mechano-growth factor, and myostatin) and other muscle genes.
IGF-1, MGF, and insulin activate the P13K, PKB or AKT mTOR pathway: Enhances protein synthesis via increased translational initiation and the synthesis of ribosomal proteins for ribosome biogenesis.
- Availability of essential amino acids activates mTOR signaling.
- Increased energy demand sensed by AMPK inhibits mTOR.
**IGF-1, MGF, myostatin, and various other factors regulate proliferation and differentiation of satellite cells.

Exercise activates signal transduction pathways via growth factors and hormones binding to the membrane (step 1).
Calcium concentration changes, mechanical stretch, energy status of the cell, hypoxia, cell damage, and injury affect these signal transduction pathways (step 2).
Numerous signal transduction proteins are signaled mainly by covalent phosphorylation.
Nuclear localization signal is activated and translocated into the nucleus.
Signaling protein acts as a transcription factor or activates transcription factors that bind regulatory DNA sequences.
Skeletal muscle genes are controlled by several regulatory elements.
Exercise-induced effects include the expression of growth factors, muscle contractile protein changes, and satellite cell proliferation.
Mitochondrial biogenesis depending on what process is activated.
Apoptosis (cell death) can occur in extreme cases.