Aberrant developmental titin splicing and dysregulated sarcomere length in Thymosin β4 knockout mice.

Smart N, Riegler J, Turtle CW, Lygate CA, McAndrew DJ, Gehmlich K, Dubé KN, Price AN, Muthurangu V, Taylor AM, Lythgoe MF, Redwood C, Riley PR

Journal of molecular and cellular cardiology30 Nov 2016Cited by 12 (Europe PMC)

PMID27914791PMCIDPMC5319848DOI10.1016/j.yjmcc.2016.10.010PepBankPUB-27914791

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Summary

Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components, including titin, undergo an isoform transition to adjust ventricular filling. Many sarcomeric genes have been implicated in congenital cardiomyopathies, such that understanding developmental sarcomere transitions will inform the aetiology and treatment. We sought to determine whether Thymosin β4 (Tβ4), a peptide that regulates the availability of actin monomers for polymerization in non-muscle cells, plays a role in sarcomere assembly during cardiac morphogenesis and influences adult cardiac function. In Tβ4 null mice, immunofluorescence-based sarcomere analyses revealed shortened thin filament, sarcomere and titin spring length in cardiomyocytes, associated with precocious up-regulation of the short titin isoforms during the postnatal splicing transition. By magnetic resonance imaging, this manifested as diminished stroke volume and limited contractile reserve in adult mice. Extrapolating to an in vitro cardiomyocyte model, the altered postnatal splicing was corrected with addition of synthetic Tβ4, whereby normal sarcomere length was restored. Our data suggest that Tβ4 is required for setting correct sarcomere length and for appropriate splicing of titin, not only in the heart but also in skeletal muscle. Distinguishing between thin filament extension and titin splicing as the primary defect is challenging, as these events are intimately linked. The regulation of titin splicing is a previously unrecognised role of Tβ4 and gives preliminary insight into a mechanism by which titin isoforms may be manipulated to correct cardiac dysfunction.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study6

2 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Mechanism
In an in vitro cardiomyocyte model, addition of synthetic Tβ4 corrected the altered postnatal titin splicing.
In plain wordsIn cells, adding synthetic thymosin β4 corrected the abnormal splicing of titin.
Peptide
Thymosin beta-4 (human)
Outcome
Not applicableTitin splicing in an in vitro cardiomyocyte model
Study
n: not reported in source
in vitro cardiomyocyte model
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Extrapolating to an in vitro cardiomyocyte model, the altered postnatal splicing was corrected with addition of synthetic Tβ4, whereby normal sarcomere length was restored.
Show in the study text Report a problemFND-2791479105
02LabIn vitro (cells)Mechanism
In an in vitro cardiomyocyte model, addition of synthetic Tβ4 restored normal sarcomere length.
In plain wordsIn cells, adding synthetic thymosin β4 restored normal sarcomere length.
Peptide
Thymosin beta-4 (human)
Outcome
IncreaseSarcomere length in an in vitro cardiomyocyte model
Study
n: not reported in source
in vitro cardiomyocyte model
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Extrapolating to an in vitro cardiomyocyte model, the altered postnatal splicing was corrected with addition of synthetic Tβ4, whereby normal sarcomere length was restored.
Show in the study text Report a problemFND-2791479106

Natural levels measured4

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

03AnimalEndogenous levelAnimal study (in vivo)Mechanism
In mice lacking their own Tβ4, cardiomyocytes had shortened thin filament, sarcomere and titin spring length.
In plain wordsIn mice without their own thymosin β4, heart muscle cells had shorter sarcomeres and titin springs.
Peptide
Thymosin beta-4 (human)
Outcome
DecreaseThin filament, sarcomere and titin spring length in Tβ4 null cardiomyocytes
Study
mousen: not reported in source
Tβ4 null mice
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
In Tβ4 null mice, immunofluorescence-based sarcomere analyses revealed shortened thin filament, sarcomere and titin spring length in cardiomyocytes, associated with precocious up-regulation of the short titin isoforms during the postnatal splicing transition.
This result measures the body's own Thymosin beta-4 (human). Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-2791479101
04AnimalEndogenous levelAnimal study (in vivo)Mechanism
In mice lacking their own Tβ4, short titin isoforms were up-regulated early during the postnatal splicing transition.
In plain wordsIn mice without their own thymosin β4, short forms of titin appeared too early after birth.
Peptide
Thymosin beta-4 (human)
Outcome
IncreaseShort titin isoform expression during postnatal splicing transition in Tβ4 null mice
Study
mousen: not reported in source
Tβ4 null mice
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
In Tβ4 null mice, immunofluorescence-based sarcomere analyses revealed shortened thin filament, sarcomere and titin spring length in cardiomyocytes, associated with precocious up-regulation of the short titin isoforms during the postnatal splicing transition.
This result measures the body's own Thymosin beta-4 (human). Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-2791479102
05AnimalEndogenous levelAnimal study (in vivo)Efficacy outcome
In adult mice lacking their own Tβ4, magnetic resonance imaging showed diminished stroke volume.
In plain wordsIn adult mice without their own thymosin β4, the heart pumped less blood per beat.
Peptide
Thymosin beta-4 (human)
Outcome
DecreaseStroke volume in adult Tβ4 null mice
Study
mousen: not reported in source
Tβ4 null mice
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
By magnetic resonance imaging, this manifested as diminished stroke volume and limited contractile reserve in adult mice.
This result measures the body's own Thymosin beta-4 (human). Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-2791479103
06AnimalEndogenous levelAnimal study (in vivo)Efficacy outcome
In adult mice lacking their own Tβ4, magnetic resonance imaging showed limited contractile reserve.
In plain wordsIn adult mice without their own thymosin β4, the heart had less ability to increase its pumping.
Peptide
Thymosin beta-4 (human)
Outcome
DecreaseContractile reserve in adult Tβ4 null mice
Study
mousen: not reported in source
Tβ4 null mice
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
By magnetic resonance imaging, this manifested as diminished stroke volume and limited contractile reserve in adult mice.
This result measures the body's own Thymosin beta-4 (human). Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-2791479104

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 01:52 UTC
Study results updated
Version 1
12 Oct 2026, 18:17 UTC
First added · source update from Europe PMC

Subjects

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