Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibers

Abstract

The combined effects of dexamethasone treatment (1 mg/Kg/day) plus denervation (DEX-DEN), were studied at 7, 13, and 28 days by microscopic, biochemical, and physiological techniques in plantaris and soleus muscles of adult rats. The results were compared with corresponding dexamethasone-treated (DEX) and denervated (DEN) muscles and appropriate controls. There was a significantly more marked atrophy of all fiber types in the DEX-DEN plantares at 7 and 13 days than in either DEX or DEN muscles. The degree of atrophy was greatest in type 2B fibers in DEX-DEN plantares. Electron microscopy revealed a severe preferential depletion of thick myofilaments in DEX-DEN plantares and solei but not in DEX or DEN muscles. The thick myofilament depletion in DEX-DEN muscles occurred in addition to a severe overall reduction of myofibrillar caliber. Gel electrophoresis showed a marked preferential decrease of myosin heavy chain in DEX-DEN plantares and solei, but not in either DEX or DEN muscles. Myosin light chains were also markedly reduced in DEX-DEN plantares and solei. In vitro physiological studies showed a marked reduction of the denervation-induced twitch potentiation in DEX-DEN solei. Maximal tetanic tension (20 Hz stimulation) per gram weight of muscle as well as the twitch-tetanus ratio was significantly reduced only in DEX-DEN solei in relation to controls. Myosin depletion in DEX-DEN muscles may be due to a severe preferential inhibition of its synthesis coupled with an accelerated catabolism.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…Loss of muscle action potentials can be easily modeled by cutting the sciatic nerve to denervate leg muscles (FIGURE 13). A rat model of acute CIM using denervation was first developed over 20 yr ago (466,597). The model involves pairing loss of muscle activity (by denervation) with systemic administration of corticosteroids (FIGURE 13).…”

“…The features recreated by the rat model include (FIGURE 13): 1) dramatic atrophy of muscle fibers (377,466,496,597), 2) preferential/selective loss of myosin (377,466,496,597), 3) disorganization of sarcomeres (377,466), and 4) electrical hypoexcitability (580 -582).…”

Mechanisms of Neuromuscular Dysfunction in Critical Illness

“…Investigation into the causes of muscle inexcitability has been carried out in a rat model of CIM that was established 20 years ago [41,42]. In that model the muscles in one leg are denervated by cutting the sciatic nerve to mimic neuromuscular blocking agents, and this is followed by 7-10 days of high dose corticosteroids.…”

Upregulation of the CaV1.1-ryanodine receptor complex in a rat model of critical illness myopathy

“…These include selective loss of myosin (10,30,31,40,43,44,53), disorganization of sarcomeres (10,53), dramatic muscle atrophy (28), and electrical inexcitability of muscle (46,49). All of these features occur in the steroid denervation rat model of the disease (38,40,48,50). It thus appears that the steroid-denervation rat model of CIM recreates all of the contributors to weakness found in patients.…”

“…Most animal studies of CIM have been carried out in a rat model that involves pairing muscle inactivity, induced by denervation, with systemic administration of corticosteroids (50). The model was established to mimic the clinical situation in patients who develop CIM following infusion of neuromuscular blocking agents and corticosteroids (10,36).…”