Passive tension (i.e. stretch) is a primary growth regulator in skeletal and cardiac muscle. Stretch stimulates muscle growth while decreased tension leads to muscle atrophy. The mechanism which couples stretch to growth or atrophy is unknown. The objective of this project is to study the molecular mechanisms by which passive tension regulates muscle protein synthesis rates. We will utilize new computerized Mechanical Cell Stimulator devices to place tissue cultured cells under repetitive passive tensions. Mechanical stimulation of differentiated avian skeletal muscle cells increases messengers for mechanical stimulation of cell growth in this tissue culture model system. PGs are also second messengers for a number of defined growth factors where they alter cell growth by generating additional messengers such as altered calcium fluxes, cyclic nucleotides, and phosphoinositides. We intend to use the Mechanical Cell Stimulator systems to address two important questions: (1) how does mechanical stimulation of muscle cells increased their PG production; and (2) which second messengers couple stretch-induced PGs to muscle protein synthesis rates? To address question 1, the activity of two enzymes (phospholipase A2 and phospholipase C) responsible for providing the precursor of PGs (arachidonic acid) will be assayed biochemically following various patterns of mechanical stimulation. In the second part of this project we will analyze the relationship of stretch-induced PGs to altered calcium fluxes, cyclic nucleotide levels, and phosphoinositides using radioactive tracers, radioimmunoassays, and immunohistochemical techniques. The relationship of these second messengers to total muscle protein synthesis rates and the synthesis of specific proteins will be studied. The results from these studies may lead to a better understanding of the molecular signaling processes regulating muscle cell growth by stretch. This knowledge might lead to the development of new pharmacological agents to limit skeletal muscle wasting in patients with limited mobility such as paraplegics and the elderly. It could also lead to nw 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 #
5R01AR039998-03
Application #
3160248
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1989-06-20
Project End
1992-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
3
Fiscal Year
1991
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
Vandenburgh, H H (1992) Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol 262:R350-5
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; 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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