Fast skeletal muscle myosin II

Fast skeletal muscle myosin II is a hexameric motor protein complex primarily composed of two heavy chains (encoded by MYH1, MYH2, or MYH4) and four light chains, which drives the rapid contraction of fast-twitch skeletal muscle fibers [1, 4]. It functions as an ATPase, utilizing the energy from ATP hydrolysis to undergo conformational changes that pull on actin filaments, generating mechanical force [2, 4]. This protein is a key therapeutic target in neuromuscular disorders; for instance, in Duchenne muscular dystrophy (DMD), selective inhibition of fast skeletal myosin II can reduce the mechanical stress on dystrophin-deficient membranes, thereby preventing contraction-induced muscle damage [5]. In conditions like spasticity following a stroke or spinal cord injury, overactivity of these myosin isoforms leads to pathological muscle stiffness and impaired movement [4, 8]. Investigational drugs such as sevasemten (EDG-5506) and MPH-220 are designed to selectively inhibit these fast isoforms to provide therapeutic benefits while sparing cardiac and slow-twitch muscle functions [4, 5, 7]. These small molecules typically act as allosteric inhibitors that stabilize the myosin head in a low-affinity actin-binding state, effectively modulating muscle power and protecting muscle fibers from degeneration [1, 4]. Clinical development of these inhibitors focuses on improving mobility and muscle health in patients with genetic myopathies or neurological injuries [3, 5].

Other names

Fast skeletal myosin-2Fast-twitch skeletal muscle myosin IIMyosin heavy chain 1 (MYH1)Myosin heavy chain 2 (MYH2)Myosin heavy chain 4 (MYH4)Fast skeletal muscle myosin heavy chain

Selective allosteric inhibition of the ATPase activity of fast skeletal muscle myosin II isoforms. These inhibitors bind to the myosin motor domain and stabilize it in a weak actin-binding (pre-powerstroke) state, which reduces the number of force-generating cross-bridges and decreases overall muscle contractility.