Tropomyosin 3 expression leads to hypercontractility and attenuates myofilament length-dependent Ca(2+) activation.
Tropomyosin (TM), an integral component of the thin filament, is encoded by three striated muscle isoforms: alpha-TM, beta-TM, and TPM 3. Although the alpha-TM and beta-TM isoforms are well characterized, less is known about the function of the TPM 3 isoform, which is predominantly found in the slow-twitch musculature of mammals. To determine its functional significance, we ectopically expressed this isoform in the hearts of transgenic mice. We generated six transgenic mouse lines that produce varying levels of TPM 3 message with ectopic TPM 3 protein accounting for 40-60% of the total striated muscle tropomyosin. The transgenic mice have normal life spans and exhibit no morphological abnormalities in their sarcomeres or hearts. However, there are significant functional alterations in cardiac performance. Physiological assessment of these mice by using closed-chest analyses and a work-performing model reveals a hyperdynamic effect on systolic and diastolic function. Analysis of detergent-extracted fiber bundles demonstrates a decreased sensitivity to Ca(2+) in force generation and a decrease in length-dependent Ca(2+) activation with no detectable change in interfilament spacing as determined by using X-ray diffraction. Our data are the first to demonstrate that TM isoforms can affect sarcomeric performance by decreasing sensitivity to Ca(2+) and influencing the length-dependent Ca(2+) activation.
Pieples
Kathy
K
Department of Molecular Genetics, Biochemistry, and Microbiology, College of Medicine, University of Cincinnati, Ohio 45267-0529, USA.
Arteaga
Grace
G
Solaro
R John
RJ
Grupp
Ingrid
I
Lorenz
John N
JN
Boivin
Greg P
GP
Jagatheesan
Ganapathy
G
Labitzke
Erin
E
DeTombe
Pieter P
PP
Konhilas
John P
JP
Irving
Thomas C
TC
Wieczorek
David F
DF
D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D007536:Isomerism; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D014335:Tropomyosin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D012333:RNA, Messenger; C411923:Tpm3 protein, mouse; D014335:Tropomyosin; D002118:Calcium