The roles of disuse and loss of neurotrophic function in denervation atrophy of skeletal muscle

Abstract

Denervated muscle fibers are characterized by a lowered resting membrane potential (RMP), increased extrajunctional acetylcholine (ACh) sensitivity, and decreased junctional acetylcholinesterase (AChE) activity. Whether these changes in denervated muscle result from cessation of contractile activity, from interruption of axonal transport, or from both is not known. Experiments were therefore designed to analyze whether or not the denervation changes could be ascribed solely to the loss of contractile activity. In one experiment, the hemidiaphragm of the rat was rendered quiescent for 1 to 3 weeks either by spinal hemisection at C2 (disuse) or by unilateral phrenicotomy (denervation). After denervation there was a spread of ACh sensitivity to extrajunctional regions, a decline in RMP, and a reduction in 16 S AChE (a measure of junctional AChE activity). Comparable changes did not occur after spinal hemisection, and we therefore conclude that inactivity alone does not induce these changes in denervated muscle. In another experiment, rats were chronically paralyzed by repeated administration of d-tubocurarine. During this time the extensor digitorum longus muscle of one hind limb was denervated. After 6 h of immobilization by d-tubocurarine, the RMP of denervated muscle fibers was significantly reduced whereas that of the contralateral innervated muscle fibers was unchanged. This result supports the previous interpretation, viz., that the change in RMP of denervated muscle fibers cannot be attributed solely to muscle inactivity. Experiments by others have shown that chronic disuse causes changes that are qualitatively but not quantitatively equivalent to those of denervation. Those observations, together with the present results, enable us to conclude that inactivity does not initiate the changes in extrajunctional ACh sensitivity, RMP, and junctional AChE activity seen in denervated muscle and that these properties of muscle are normally regulated by axonally transported neurotrophic influences.