The musculoskeletal system comprises one of the major tissue/organ systems in the body. The three main types of muscle tissue are skeletal, cardiac and smooth muscle groups.[1][2][3] Skeletal muscle attaches to the bone by tendons, and together they produce all the movements of the body.  The skeletal muscle fibers are crossed with a regular pattern of fine red and white lines, giving the muscle a distinctive striated appearance. Hence they are also known as striated muscle.[4][5][6][7][8]

The skeletal muscle is one of the three significant muscle tissues in the human body. Each skeletal muscle consists of thousands of muscle fibers wrapped together by connective tissue sheaths. The individual bundles of muscle fibers in a skeletal muscle are known as fasciculi. The outermost connective tissue sheath surrounding the entire muscle is known as epimysium. The connective tissue sheath covering each fasciculus is known as perimysium, and the innermost sheath surrounding individual muscle fiber is known as endomysium.[9] Each muscle fiber is comprised of a number of myofibrils containing a number of myofilaments. When bundled together, all the myofibrils get arranged in a unique striated pattern forming sarcomeres which are the fundamental contractile unit of a skeletal muscle. The two most significant myofilaments are actin and myosin filaments which are arranged distinctively to form various bands on the skeletal muscle. The stem cells which differentiate into mature muscle fibers are known as satellite cells which can be found between the basement membrane and the sarcolemma (the cell membrane surrounding the striated muscle fiber cell).[10] When stimulated by growth factors, they differentiate and multiply to form new muscle fiber cells.[11]

The primary functions of the skeletal muscle take place via its intrinsic excitation-contraction coupling process. As the muscle is attached to the bone tendons, the contraction of the muscle leads to movement of that bone that allows for the performance of specific movements. The skeletal muscle also provides structural support and helps in maintaining the posture of the body. The skeletal muscle also acts as a storage source for amino acids that can be used by different organs of the body for synthesizing the organ-specific proteins.[12] The skeletal muscle also plays a central role in maintaining thermostasis and acts as an energy source during starvation.[9]

Distinct transcriptional mechanisms and specific gene regulatory activity control the differentiation of muscle fibers.[13]During embryogenesis, it is the para-axial mesoderm that undergoes stepwise differentiation to generate the muscle tissue. The para-axial mesoderm on either side of the neural tube starts to differentiate and undergoes segmentation to form the somites. The somites get stimulated by the myogenic regulatory factors to differentiate into a dermomyotome and sclerotome. These regulatory factors include the Wnt, Shh and BMP4 proteins. The neural tube and the surface ectoderm are the primary sources of Wnt proteins, the Shh proteins(Sonic Hedge Hog) source from Notochord, and the lateral mesoderm plate produces the BMP4 protein.[14] The lateral aspect of the dermomyotome undergoes epithelial to mesenchymal transition as it proceeds to migrate on the ventral side to form a unique myotome below the dermatome.

The myotome then differentiates to form the skeletal muscles in the body after receiving stimulation from the Sonic Hedgehog (Shh) signaling molecule from the notochord that results in the Myf5 expression and subsequent differentiation.[15] The dorsomedial aspect of the myotome differentiates into epaxial myotome giving rise to back muscles. The ventrolateral aspect differentiates into hypaxial myotome that gives rise to muscles of the body wall.

Several signaling molecules like the Wnt and the BMP along with some transcription factors like Sine Oculis homeobox are responsible for this differentiation. The development of skeletal muscles in the limb and the trunk depends on the expression of MyoD and Myf5 and their effects on the different myoblasts.[16] These embryonic myoblasts undergo further differentiation to form the primary muscle fibers and eventually secondary myofibers by the union of myoblasts in the fetus. After birth, the satellite cells act as stem cells and are responsible for the further growth and development of skeletal muscles.

The main artery or the primary artery supplying blood to the skeletal muscle courses parallel to the longitudinal axis of the muscle fiber.[17] The primary artery gives off tributaries which are known as feed arteries, that are perpendicular to the primary artery and proceed towards the external connective tissue sheath of the muscle fiber called perimysium.[18] The feed artery branches into primary arterioles which after two more orders of branching gives rise to transverse arterioles, which in turn give rise to terminal arterioles.[19] The terminal arterioles are the final vascular branches, and they perfuse the capillaries that are present within the endomysium and travel parallel to the longitudinal axis of the muscle fiber. The terminal arteriole along with the capillaries that it supplies is known as a microvascular unit, and it is the smallest unit in the entire skeletal muscle where the blood flow can be regulated.

Lymph capillaries originate in skeletal muscle in the microvascular unit within the endomysium near the main capillary bed and drain the tissue fluid. These capillaries merge with each other to form the lymphatic vessels as they drain out the tissue fluid. These lymphatic vessels go through the perimysium and join with the larger lymphatic vessels. Unlike the blood vessels, the wall of the lymph vessels within the muscle does not have contractile property due to lack of smooth muscles(in the wall), so they depend on the muscle movement and arteriolar pulsations to drain the lymph out.

The neuronal innervation of a skeletal muscle typically comprises of sensory nerve fibers, motor nerve fibers, and the neuromuscular junction. The nerve fibers are composed of myelinated as well as non-myelinated nerve fibers. The cell bodies of the neurons give rise to large axons which are generally unbranched and travel to the target muscles for innervation. Near the target muscle, the axons divide into multiple smaller branches to innervate multiple muscle fibers. The motor nerve terminal has abundant mitochondria, endoplasmic reticulum and numerous membrane-bound synaptic vesicles containing neurotransmitter- acetylcholine.[20] Once the action potential travels to the neuromuscular junction, there occurs a series of processes culminating into the fusion of the membrane of the synaptic vesicles with the presynaptic membrane and subsequent release of the neurotransmitter into the synaptic cleft.[21] [22]

The postsynaptic membrane of the muscle fibers has a massive concentration of neurotransmitters (AchR) receptors. These receptors are transmembrane ligand-gated ion channels.[23] Once the neurotransmitter activates these ion channels, there is a rapid depolarization of the motor end plate, which initiates an action potential in the muscle fiber resulting into muscle contraction.[21]