Skeletal Muscle Function
Mobility, movement and skeletal muscle
Skeletal muscles account for up to 40% of body mass in humans and exhibit a fascinating range of diversity and adaptability. This inherent flexibility enables our muscles to adjust to diverse situations and types of voluntary movements, underscoring their crucial role in our daily activities. Body movement is ensured by the coordinated efforts of the musculoskeletal and nervous systems. Skeletal muscles generate the necessary force for movement, bones provide structural support, and nerves transmit signals that coordinate these actions. Muscles also provide support and stability to joints, reducing the risk of joint injuries. This intricate system enables basic locomotion and supports complex movements, ensuring that the body can perform a wide range of physical activities efficiently and effectively. This is particularly important for maintaining independence in older adults, as adequate muscle function, encompassing both lower and upper limb strength, prevents falls and injuries by enhancing balance and coordination. Furthermore, muscle strength and endurance are essential for cardiovascular health, as they improve circulation and reduce the workload on the heart. Finally, skeletal muscles ensure vital functions, such as respiration and thermoregulation, by contracting, and are key regulators of whole-body metabolism. Hence, maintaining muscle function is critical for overall health and well-being.
Functions of skeletal muscles
Molecular networks sustaining muscle homeostasis
Muscle contraction relies on complex intracellular protein networks and environmental crosstalk.
Skeletal muscles comprise numerous multinucleated muscle fibers that run the entire muscle length. Each muscle fiber is innervated by a single motor neuron allowing precise muscle fiber contraction. Muscle fibers differ in force, contraction speed, fatigue resistance, and metabolism. Skeletal muscles involved in maintaining posture contain thinner fatigue-resistant slow fibers, which are always in use. Larger fast fibers that generate more force are recruited during intense efforts but fatigue more quickly. Engaging in resistance training significantly boosts the force-generating capacity of fast fibers, often leading to hypertrophy. Conversely, endurance training enhances the fatigue resistance of these fibers by promoting mitochondrial biogenesis and improving aerobic capacity. The contractile apparatus of muscle fibers, organized in sarcomeres, consists of various key proteins, including actin and myosin. Skeletal muscle contraction is controlled by the motor neuron, which releases acetylcholine at the neuromuscular junction and triggers the propagation of action potentials along the muscle fiber. These action potentials induce a massive and synchronized release of calcium from internal stores, which allows the interactions of actin and myosin, the shortening of sarcomeres and, consequently, muscle fiber contraction. Several myopathies are due to mutations in the genes encoding proteins involved in calcium signals or muscle architecture, leading to muscle dysfunction and eventually muscle cell death.
Organization of skeletal muscles
Muscle fibers are derived from a mesenchymal stem cell population that undergoes extensive migration and proliferation during fetal development, before settling in dedicated areas in the tissue. The migration and proliferation of muscle precursors (or myoblasts) are guided by growth factors and extracellular matrix proteins within the connective tissue. Myoblasts express receptors for the extracellular matrix protein fibronectin, and its deposition is subsequently used as a scaffold for the alignment of muscle fibers. Once the differentiation program is initiated, myoblasts align and fuse into large multinucleated myotubes. The fusion process is tightly controlled by TGFb family cytokines, which provide a brake on the fusion process. This maintains a healthy balance of myotubes and myoblasts, which will give rise to the muscle stem cell pool. The formed muscle fibers are physically anchored to the extracellular laminin-containing basement membrane. This basement membrane allows the connection of the muscle fiber to its attached tendons and ligaments. Moreover, it contains critical signaling components to guide motor neurons during muscle innervation.
Skeletal muscles are highly plastic tissues
Skeletal muscle homeostasis is tightly dependent on proteostasis, which corresponds to the balance between protein anabolism and catabolism. Increasing protein synthesis is commonly believed to induce muscle growth, while protein degradation would drive muscle atrophy. However, evidence in the last decades has uncovered the importance of sustaining catabolic processes to preserve muscle quality and function. Perturbation in proteostasis, in either direction, is hence associated with muscle atrophy and/or dysfunction in several pathological conditions. In this context, increased activity of the anabolic axis governed by Akt and mTORC1, as well as blockage of the autophagy and proteasome catabolic processes, have been pointed as central players in aging-dependent alterations of skeletal muscle.
Skeletal muscle maintenance is also ensured by its high regenerative capacity. Muscle regeneration resembles muscle development in several aspects. The process involves resident muscle stem cells, characterized by the expression of the myogenic transcription factor Pax7. Muscle stem cells are located in a niche between the sarcolemma and the basal lamina surrounding the myofiber and are maintained in a mitotically cell-cycle-arrested state known as quiescence. Upon tissue injury, muscle stem cells exit quiescence and enter the myogenic program, successively activating, proliferating, differentiating and fusing into new muscle fibers. The process ensures the replacement or repair of damaged myofibers. Notably, a small population of activated muscle stem cells self-renews and returns into quiescence, hence maintaining muscle stem cell pool and allowing ulterior regeneration. Skeletal muscle injuries can result from a variety of events, including direct trauma such as muscle tears, indirect insults such as strains, and degenerative diseases such as muscular dystrophies. Skeletal muscle regeneration is a complex process involving immune, fibrotic, vascular and myogenic cells that appear with distinct temporal and spatial kinetics after muscle injury. Skeletal muscle can regenerate completely in response to minor injuries such as strains. In contrast, after severe injury, muscle healing is incomplete, often leading to the formation of fibrotic tissue that impairs muscle function. Specifically, in muscular dystrophies, such as Duchenne Muscular Dystrophy, skeletal muscles cope with unsynchronized and repeated cycles of degeneration/regeneration, which leads to the development of muscle fibrosis.