Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle
Justin M. Percival, Kendra N.E. Anderson, Paul Huang, Marvin E. Adams, Stanley C. Froehner
Justin M. Percival, Kendra N.E. Anderson, Paul Huang, Marvin E. Adams, Stanley C. Froehner
View: Text | PDF
Research Article Muscle biology

Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle

Abstract

Signaling via the neuronal NOS (nNOS) splice variant nNOSμ is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOSμ is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOSβ, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOSμ alone, muscles missing both nNOSμ and nNOSβ were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOSμ and nNOSβ were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOSβ is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS microdomains in skeletal muscle, created by the differential targeting of nNOSμ to the sarcolemma and nNOSβ to the Golgi. We have previously shown that sarcolemmal nNOSμ matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOSβ simultaneously modulates the ability of skeletal muscle to maintain force production during and after exercise. We conclude therefore that nNOS splice variants are critical regulators of skeletal muscle exercise performance.

Authors

Justin M. Percival, Kendra N.E. Anderson, Paul Huang, Marvin E. Adams, Stanley C. Froehner

×

Figure 5

nNOS splice variants differentially regulate contraction-induced fatigue and postexercise force recovery.

Options: View larger image (or click on image) Download as PowerPoint
nNOS splice variants differentially regulate contraction-induced fatigue...
TA muscles were subjected to a series of maximal tetanic stimulations every 2 seconds for 4 minutes to simulate exercise. Muscles were rested, then maximally stimulated once at 1 and 5 minutes to measure postexercise strength recovery. Representative traces for each nNOS mutant fitted with exponential decay curves are shown. TA muscles of α-syntrophin (α-SYN) knockout mice (green diamonds) or KN1 muscles (yellow circles) exhibit normal muscle fatigue indistinguishable from WT controls (blue squares). In contrast, KN2 muscles (red triangles) exhibited significantly increased susceptibility to contraction-induced muscle fatigue, with force output levels leveling off at approximately 60% lower than those from WT, KN1, and α-syntrophin muscles. Force recovery at 1 and 5 minutes was significantly decreased by approximately 50% after simulated exercise, indicating substantial postexercise weakness. Po is the tetanic force in millinewtons generated at time t during the stimulation protocol. Pi is the initial force output in millinewtons at time 0, at the beginning of the experiment.