Attenuation of skeletal muscle atrophy via protease inhibition

• Published in: Journal of applied physiology (1985) 2005-11, Vol.99 (5), p.1719-1727
• Main Authors: Morris, Carl A, Morris, Linda D, Kennedy, Ann R, Sweeney, H. Lee
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Body Weight; Cell Size - drug effects; Desmin - metabolism; Fundamental and applied biological sciences. Psychology; Hindlimb Suspension - physiology; Inhibitor drugs; Male; Mice; Mice, Inbred C57BL; Muscle Contraction - physiology; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - enzymology; Muscle, Skeletal - pathology; Muscular Atrophy - drug therapy; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular system; Organ Size; Peptide Hydrolases - metabolism; Protease inhibitors; Rodents; Serine Proteinase Inhibitors - pharmacology; Talin - metabolism; Trypsin Inhibitor, Bowman-Birk Soybean - pharmacology
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01419.2004

1 Department of Physiology and the Pennsylvania Muscle Institute and 2 Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Submitted 27 December 2004 ; accepted in final form 20 June 2005 Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3–14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity. hindlimb unloading; protease inhibitors; Bowman-Birk inhibitor; protein degradation Address for reprint requests and other correspondence: H. L. Sweeney, Dept. of Physiology and the Pennsylvania Muscle Institute, Univ. of Pennsylvania School of Medicine, A-700 Richards Bldg., 3700 Hamilton Walk, Philadelphia, PA 19104–6085 (e-mail: lsweeney{at}mail.med.upenn.edu )