Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise | Journal of Applied Physiology

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• Historically, mechanical stimuli became a research focus when researchers discovered in the 1950s that cancer cells can grow on soft agar without anchorage whereas most non-cancer cells cannot. Researchers then discovered from the 1970s onwards that cells anchor the extracellular matrix through focal adhesion complexes that include proteins such as vinculin, talin, and integrins as well as kinases including focal adhesion kinase or integrin-linked kinase (Ilk). Focal adhesions not only anchor cells on a substrate but also connect the exterior mechanically to the cytoskeleton and can sense and trigger adaptations to mechanical stimuli (72, 145).

• exercise-induced muscle damage is probably not essential for hypertrophy,

• Mechanical signals are arguably the most intuitive hypertrophy stimuli.

• Third, mechanical load is also the key candidate hypertrophy stimulus that links human resistance exercise to skeletal muscle hypertrophy. This is because high forces distinguish hypertrophy-inducing resistance exercise from low load endurance exercise that triggers little or no hypertrophy. However, as we will address later, mechanical loading does not need to be excessive for muscle hypertrophy stimulation. Loads as low as ≈30% of the 1RM seem sufficient to trigger a near maximal hypertrophic response (5a).

• This study showed greater muscle protein synthesis (labeled the fractional synthetic rate) at higher loads peaking between 60 and 90% of the 1RM (84). A caveat to these findings is that, in an effort to equate workload, participants did not exercise to failure, especially when using lighter loads.

• concluded that lower load (≤60% 1RM) resistance training causes a similar degree of hypertrophy as higher load (>60%) resistance training (135)

• In untrained individuals even submaximal aerobic training (i.e., low mechanical load exercise) (77) or very low loads (16% of the 1RM) can increase muscle protein synthesis somewhat (4).

• In summary, a large amount of mainly indirect evidence suggests that mechanical load is a key hypertrophy stimulus associated with resistance exercise. However, the actual loads do not need to be excessive as loads of ≈30% of 1RM seem sufficient to trigger near maximal hypertrophic gains.

• Single, skinned human type I and IIa muscle fibers have been reported to generate forces of 532 ± 208 and 549 ± 262 µN, respectively (81), with each myosin head contributing ≈6 pN (120)

• Nonmuscle cells can also produce force through their actin-cytoskeleton, but the forces are lower. For example, fibroblasts have been reported to produce forces of 16 ± 7 µN/cell (79). While these force values are just examples, they demonstrate that striated muscle fibers are unique in their high force-generating ability.

• The forces generated by the sarcomeres of a muscle fiber are transmitted to tendons and bones via two force-transducing systems: 1) forces are transmitted longitudinally from one end of a muscle fiber to the other end; and 2) forces are additionally transmitted laterally from the sarcomere through the muscle fiber membrane (sarcolemma) to the extracellular matrix (141) via costameres (73), which are the focal adhesion equivalent in muscle fibers.

• Costameres are the functional equivalent of focal adhesions in skeletal muscle.

• There are two costamere complexes, which are the dystrophin-glycoprotein complex and the vinculin-talin-integrin complex.

• In cultured C2C12 myotubes, IGF-1 can increase FAK Tyr397 autophosphorylation and FAK is required for IGF-1-induced hypertrophy and tuberous sclerosis 2 (Tsc2), mTOR, and S6K1 signaling (28)

• phosphorylated FAK Tyr397 was increased 60–90 min posteccentric exercise when compared with concentric bout exclusively at the distal site of the vastus lateralis muscle (43). Generally, while FAK might help to regulate muscle size, it is unclear whether FAK contributes to the hypertrophy adaptation to resistance exercise.

• Recently, it has been shown that mechanical stimuli in the form of attachment to either a soft or stiff substrate promote the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidic acid. This synthesis of phosphatidic acid was catalyzed by phospholipase Cγ1 (PLCγ1) and activated the Hippo pathway effectors Yap (Yes-associated protein 1, gene Yap1) and its paralogue Taz (gene Wwtr1) (98).

• While these papers suggest no link to mTORC1 and even demonstrate that Yap can cause hypertrophy with rapamycin treatment (52), there are known links between Yap and mTORC1.

• This is then usually followed by a local inflammatory response, disturbed Ca2+ regulation, activation of protein breakdown, and increased levels of proteins such as creatine kinase in the blood that escape or are secreted from damaged muscle fibers (23, 76, 115)

• The higher the exercise load, the more ATP will be hydrolyzed per second and the faster PCr, lactate, and the pH will change. Thus, during high-intensity resistance exercise, the PCr concentration and the pH will drop more per second than during low load resistance exercise (143, 144, 158). However, as metabolic stress either causes fatigue or is associated with it (5), metabolic stress will be higher at the end of a set with low loads because we can lift a lower load with a more fatigued muscle than during a set with high loads as we can only lift a high load if fatigue and metabolic stress are low.