Browsing by Author "Kim, Min Jeong"

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    Sarcolemmal targeting of nNOS mu improves contractile function of mdx muscle
    (OXFORD UNIV PRESS, 2016) Rebolledo, Daniela L.; Kim, Min Jeong; Whitehead, Nicholas P.; Adams, Marvin E.; Froehner, Stanley C.
    Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOS mu) produced by the NOS1 gene. Skeletal muscle nNOS mu is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOS mu from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOS mu on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOS mu (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss owing to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOS mu at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including beta-dystroglycan, alpha-syntrophin and alpha-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOS mu from the sarcolemma.