Original articleUbiquitin ligases MuRF1 and MAFbx in human skeletal muscle atrophy
Introduction
The basic definition of skeletal muscle atrophy is a decrease in cell size. Atrophy can be due to a decrease in the fiber cross-sectional area or length, or both, and can also occur as a decrease in muscle mass, protein content or decreased fiber number, and loss of strength [1]. Numerous and heterogeneous pathological conditions cause human muscle atrophy [2]. Profound atrophy is often a consequence of diseases such as cancer and AIDS. Muscle immobilization, as commonly seen when a limb is placed in a cast after an orthopedic injury, causes rapid muscle loss that may require months of physical therapy to reverse. The effectiveness of glucocorticoid drugs, such as dexamethasone, is limited by muscle wasting, seen as a side-effect of these agents. Even during normal aging, there is a gradual loss of muscle mass and a diminished capacity to reverse that loss, which results in weakness and morbidity [3], [4], [5], [6], [7]. Experimental studies have proven that different conditions use common enzyme pathways, leading to muscle atrophy [5]. The primary mechanism that contributes to decreasing skeletal muscle strength and size in healthy aging is not presently known [8].
In catabolic conditions where proteolysis is increased, two specific genes for skeletal muscle atrophy, MuRf1 (muscle ring finger-1) and MAFbx (muscle atrophy F-box) (or atrogin-1), which encode ubiquitin (Ub) ligases, are upregulated. Ligases bind to and mediate ubiquitination of myofibrillar proteins for subsequent degradation during muscle atrophy and are considered as sensitive markers of muscle protein degradation by the Ub-proteasome system [9], [10].
Since there are no effective treatments for muscle atrophy, these proteins are potential targets for the pharmacological treatment of muscle atrophy [11]. We focused on similarities in the intracellular responses of human skeletal muscle atrophy by including subjects in whom a variety of diverse stimuli induce muscle atrophy. The aim of the preliminary study was to gain a better understanding of the pathological anatomy of human lower limb muscles in atrophy caused by different pathological conditions by use of histochemistry and immunolocalization of MuRF1 and MAFbx and showing that MuRF1 and MAFbx are not expressed in normal skeletal muscle.
Section snippets
Methods
Fifteen patients undergoing amputation in the distal or proximal third of the lower leg due to diverse chronic or acute conditions from March to September 2005 were divided into two groups. Group A included 12 elderly subjects (mean age 79 years, range 65–85), of whom 10 underwent amputation for vascular disease (four from complications of type 2 diabetes), one for chronic osteomyelitis four years after sustaining an exposed fracture, and one for squamous cell carcinoma of the skin on the
Histochemistry
Relationships between muscle-tendon junctions (MTJs), myofascial junctions and myofiber-myofiber (myomuscular) junctions were clearly apparent. In Group A, all specimens presented split fibers and fibers with centralized nuclei; fiber atrophy and decreased cross-sectional fiber area and length, with the presence of adipose tissue, were also observed. Group B muscle fibers had a normal appearance, with centralized nuclei.
Immunohistochemistry
Group A specimens stained for anti-MuRf1 (Fig. 1a,c; Table 1) and
Discussion
Skeletal muscle atrophy occurs as a consequence of aging, denervation, injury, joint immobilization, bed rest, glucocorticoid treatment, sepsis and cancer. Although a variety of diverse stimuli induce muscle atrophy, there is a surprising number of similarities in intracellular responses [12], [13], [14], [15], [16], [17]. Bodine and co-workers performed transcript profiling to identify candidate molecular mediators of muscle atrophy. Although several genes were upregulated in a rat model of
Acknowledgments
The authors are grateful to Ms Sandra Manzotti of the Laboratory of the Department of Orthopedics, Università Politecnica delle Marche, for the preparation of the histological sections and to Dr Silvia Modena for reviewing the English.
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