Skeletal muscle fibers differentiate before they are innervated, and some neuromuscular junctions are formed well after birth. Before innervation, the muscle fibers physiologically resemble slow (type I) cells. Acetylcholine receptors are distributed throughout the sarcolemma of these uninnervated cells and are supersensitive to that neurotransmitter. An end plate is formed when the first growing nerve terminal establishes contact with a muscle cell. The cell forms no further association with nerves, and receptors to acetylcholine become concentrated in the end plate membranes. Cells innervated by a small motor neuron form slow (type I) oxidative motor units. Fibers innervated by large motor nerves develop all the characteristics of fast (type II) motor units. Innervation produces major cellular changes, including synthesis of the fast and slow myosin isoforms, which replace embryonic or neonatal variants. Thus muscle fiber type is determined by the nerves that innervate the fiber.
An increase in muscle strength and size occurs during maturation. As the skeleton grows, the muscle cells lengthen. Lengthening is accomplished by the formation of additional sarcomeres at the ends of the muscle cells (
Fig. 12.20 ), a process that is reversible. For example, the length of a cell decreases when terminal sarcomeres are eliminated, which can occur when a limb is immobilized with the muscle in a shortened position or when improper setting of a fracture causes shortening of the limb segment. Changes in muscle length affect the velocity and extent of shortening but do not influence the amount of force that can be generated by the muscle. The gradual increase in strength and diameter of a muscle during growth is achieved mainly by hypertrophy. Doubling the myofibrillar diameter by adding more sarcomeres in parallel (hypertrophy, for example) may double the amount of force generated but has no effect on the maximal velocity of shortening. Resistance exercise can promote hypertrophy by activation of the Akt-mTOR signaling pathway and simultaneous inhibition of the forkhead box O protein (FoxO)–atrogene pathway, which results in an increase in net protein synthesis (
Fig. 12.21A ). The increase in intracellular Ca and decrease in ATP concentration can also stimulate mitochondrial biogenesis and expression of a slow muscle phenotype through activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling (see
Fig. 12.21B
Skeletal muscles have a limited ability to form new fibers (hyperplasia). These new fibers result from differentiation of satellite cells that are present in the tissues. However, major cellular destruction leads to replacement by scar tissue.
Muscles not only must be used to maintain normal growth and development but must also experience loading.
•Fig. 12.20. Effects of Growth on the Mechanical Output of a Muscle Cell. Typically,skeletalmusclecellgrowthinvolveseitherlengthening(addingmoresarcomerestotheendsofthemusclefibers)orincreasingmusclefiberdiameter(hypertrophyasaresultoftheadditionofmoremyofilaments/myofibrilsinparallelwithinthemusclefiber).Theformationofnewmusclefibersiscalledmuscle hyperplasia, anditisinfrequentinskeletalmuscle.
Muscles immobilized in a cast lose mass. In addition, space flight exposes astronauts to a microgravity environment that mechanically unloads their muscles. Such unloading leads to rapid loss of muscle mass (i.e., atrophy) and weakness. Disuse atrophy appears to involve both inhibition of protein synthesis and stimulation of protein degradation (with net activation of the FoxO-atrogene pathway). Other categories of skeletal muscle atrophy include sarcopenia (which is atrophy associated with the aging process) and cachexia (which is atrophy associated with an illness).