Passive tension induced by mechanical stretch is an important growth regulator in skeletal and cardiac muscle. Stretch and the resultant increase in tension stimulates muscle growth while decreased tension from muscle shortening leads to muscle atrophy. The mechanism which couples this physical stimulus to growth or atrophy is unknown. The objective of this project is to study the molecular mechanisms by which passive tension regulates skeletal muscle growth. We will utilize a computerized mechanical cell stimulator device to place tissue cultured avian skeletal myofibers under repetitive passive tensions. This stimulation increases myofiber growth rate and prostaglandin (PG) synthesis, and these PGs are important second messengers for stretch-induced growth of skeletal muscle. Stretch activates phospholipase A2 and D activities which provide arachidonic acid for PG synthesis. Stretch also increases the intracellular activity of prostaglandin synthase (cyclooxygenase). G proteins and protein kinase C are involved in the regulation of stretch- induced PG synthesis in the muscle cells. Our experiments are aimed at determining how stretch activates phospholipase A2, phospholipase D, and cyclooxygenase, and understanding the role of G proteins and protein kinase C in this cascade. We will examine the stretch regulation of cyclooxygenase and G proteins at both the transcriptional and post- transcriptional levels. We intend to identify the """"""""mechanosensor"""""""" molecules in the PG second messenger pathway which regulate PG synthesis and skeletal muscle cell growth. The results from these studies will lead to a better understanding of the molecular signaling processes regulating muscle cell growth by tension. This knowledge should lead to the development of new pharmacologic agents to reduce skeletal muscle wasting in patients with limited mobility such as paraplegics and the elderly. It could also lead to new treatments for stretch-induced cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR039998-04
Application #
3160245
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-06-20
Project End
1995-05-31
Budget Start
1992-06-26
Budget End
1993-05-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Miriam Hospital
Department
Type
DUNS #
039318308
City
Providence
State
RI
Country
United States
Zip Code
02906
Perrone, C E; Fenwick-Smith, D; Vandenburgh, H H (1995) Collagen and stretch modulate autocrine secretion of insulin-like growth factor-1 and insulin-like growth factor binding proteins from differentiated skeletal muscle cells. J Biol Chem 270:2099-106
Vandenburgh, H H; Shansky, J; Solerssi, R et al. (1995) Mechanical stimulation of skeletal muscle increases prostaglandin F2 alpha production, cyclooxygenase activity, and cell growth by a pertussis toxin sensitive mechanism. J Cell Physiol 163:285-94
Chromiak, J A; Vandenburgh, H H (1994) Mechanical stimulation of skeletal muscle cells mitigates glucocorticoid-induced decreases in prostaglandin production and prostaglandin synthase activity. J Cell Physiol 159:407-14
Vandenburgh, H H; Shansky, J; Karlisch, P et al. (1993) Mechanical stimulation of skeletal muscle generates lipid-related second messengers by phospholipase activation. J Cell Physiol 155:63-71
Chromiak, J A; Vandenburgh, H H (1992) Glucocorticoid-induced skeletal muscle atrophy in vitro is attenuated by mechanical stimulation. Am J Physiol 262:C1471-7
Vandenburgh, H H (1992) Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol 262:R350-5
Vandenburgh, H H; Karlisch, P; Shansky, J et al. (1991) Insulin and IGF-I induce pronounced hypertrophy of skeletal myofibers in tissue culture. Am J Physiol 260:C475-84
Vandenburgh, H H; Swasdison, S; Karlisch, P (1991) Computer-aided mechanogenesis of skeletal muscle organs from single cells in vitro. FASEB J 5:2860-7
Vandenburgh, H H; Hatfaludy, S; Karlisch, P et al. (1991) Mechanically induced alterations in cultured skeletal muscle growth. J Biomech 24 Suppl 1:91-9
Samuel, J L; Vandenburgh, H H (1990) Mechanically induced orientation of adult rat cardiac myocytes in vitro. In Vitro Cell Dev Biol 26:905-14

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