Atrophy, but not necrosis, in rabbit skeletal muscle denervated for periods up to one year

Abstract

JC. Atrophy, but not necrosis, in rabbit skeletal muscle denervated for periods up to one year. Am J Physiol Cell Physiol 292: C440 -C451, 2007; doi:10.1152/ajpcell.00085.2006.-Our understanding of the effects of long-term denervation on skeletal muscle is heavily influenced by an extensive literature based on the rat. We have studied physiological and morphological changes in an alternative model, the rabbit. In adult rabbits, tibialis anterior muscles were denervated unilaterally by selective section of motor branches of the common peroneal nerve and examined after 10, 36, or 51 wk. Denervation reduced muscle mass and cross-sectional area by 50 -60% and tetanic force by 75%, with no apparent reduction in specific force (force per cross-sectional area of muscle fibers). The loss of mass was associated with atrophy of fast fibers and an increase in fibrous and adipose connective tissue; the diameter of slow fibers was preserved. Within fibers, electron microscopy revealed signs of ultrastructural disorganization of sarcomeres and tubular systems. This, rather than the observed transformation of fiber type from IIx to IIa, was probably responsible for the slow contractile speed of the muscles. The muscle groups denervated for 10, 36, or 51 wk showed no significant differences. At no stage was there any evidence of necrosis or regeneration, and the total number of fibers remained constant. These changes are in marked contrast to the necrotic degeneration and progressive decline in mass and force that have previously been found in long-term denervated rat muscles. The rabbit may be a better choice for a model of the effects of denervation in humans, at least up to 1 yr after lesion.force; shortening velocity; electron microscopy; histochemistry MUCH OF OUR KNOWLEDGE of the effects of long-term denervation of mammalian skeletal muscle comes from experimental studies of total sciatic section in the rat (7,32,54). The mass of the affected muscles falls rapidly within 5-7 days of axotomy (11,18,22,25,55,57,58) and declines further to 30 -50% of control weight in succeeding weeks (1,5,11,14,23,41,60). After several months, muscle weight stabilizes at ϳ5-20% of control (1,13,45).Within the muscles, individual fibers show a reduction of ϳ70% in cross-sectional area (CSA) over a period of months (5,14,21,37), and over 90% (1,21,45) in the longer term. Initially, fast (type II) fibers are more susceptible to atrophy than slow (type I) fibers (5,7,32,38,48,54,59), but over more prolonged periods the fiber types atrophy to a similar extent (6, 54). Corresponding to this reduction in fiber CSA, there is a striking and progressive increase in interstitial collagen and fat (32). At the ultrastructural level, atrophic muscle fibers show evidence of disorganization, including loss or misalignment of sarcomeres, dissociation of the T system and sarcoplasmic reticulum (SR), and changes in the sarcomeric location of mitochondria (32, 51, 52).The major physiological correlate of these morphological changes is a loss of force-generati...

Skeletal muscles of hibernating brown bears are unusually resistant to effects of denervation

“…Moreover, the fiber and whole-muscle average decreases in CSA were similar in magnitude to the wet musculotendon mass data for both the LDE and CT muscles (Fig.3). In hibernating bears, this consistency indicates that the musculotendon complex composition and structure did not change drastically, such as in the case of replacement of contractile tissue with connective tissue and/or fat, which can occur following denervation (Tews et al, 1994;Ashley et al, 2007). In summeractive bears, this consistency reflects that most of the muscle mass decrease was due to loss of the contractile components.…”

“…However, we chose to section the common peroneal, which innervates the dorsiflexors, for three reasons: (1) the surgery was minimally invasive as the nerve is superficial, thus minimizing any local tissue damage (e.g. scarring) or the potential of affecting hibernation behavior; (2) previous studies have measured the seasonal changes in the dorsiflexors of hibernating wild black bears (Harlow et al, 2001;Lohuis et al, 2007), which provides a baseline from which to compare the results of this study; and (3) previous studies in other mammals have shown that denervation of the dorsiflexors produces gross atrophy (Dedkov et al, 2003;Ashley et al, 2007).…”

“…We compared the denervation responses in hibernating and summer-active bears with those of other mammals, including humans (Castro et al, 1999), laboratory rats (Dedkov et al, 2003), domestic rabbits (Ashley et al, 2007) and guinea pigs (Tomanek and Lund, 1973). Specifically, we compared our results with those of studies that: (1) measured changes in mixed fiber-type muscles (cranial tibial, tibialis anterior or vastus lateralis), because the denervation response is different for these muscles relative to that for postural, primarily slow-type muscles (Booth and Baldwin, 1995); and (2) had within-animal controls to assess the amount of atrophy, which is similar to this study.…”

Excitation-contraction coupling and mechano-sensitivity in denervated skeletal muscles

“…If, however, later stages of denervation are examined there are indications (although no hard evidence) of differences between muscles and species particularly in the time course of the atrophy (i.e. alteration after a few months in rat can be observed up to one year in humans) [2,6,52]. Skeletal muscle atrophy involves many protein systems; in this review we will focus on the more relevant changes of the excitation-contraction coupling, ECC, and mechano-transduction observed in early-and long-term denervated skeletal muscles.…”

Severely Atrophic Muscle Fibers with Nuclear Clumps Survive many Years in Permanently Denervated Human Muscle

“…It progresses during the first two years of denervation, while severe atrophy (a stage in which muscle fiber size decreases to 20-10% with respect to normal values) appears after twothree years, accompanied by a progressive degeneration of the muscle tissue [4,5]. This behaviour is not unique to humans, but it is a common feature in mammals larger than rodents [6,7].…”