Troponin T Modulates Sarcomere Length-Dependent Recruitment of Cross-Bridges in Cardiac Muscle

Journal of Experimental Biology

et al. 2011

SUMMARYDo animals know at a physiological level how much they weigh, and, if so, do they make homeostatic adjustments in response to changes in body weight? Skeletal muscle is a likely tissue for such plasticity, as weight-bearing muscles receive mechanical feedback regarding body weight and consume ATP in order to generate forces sufficient to counteract gravity. Using rats, we examined how variation in body weight affected alternative splicing of fast skeletal muscle troponin T (Tnnt3), a component of the thin filament that regulates the actin-myosin interaction during contraction and modulates force output. In response to normal growth and experimental body weight increases, alternative splicing of Tnnt3 in rat gastrocnemius muscle was adjusted in a quantitative fashion. The response depended on weight per se, as externally attached loads had the same effect as an equal change in actual body weight. Examining the association between Tnnt3 alternative splicing and ATP consumption rate, we found that the Tnnt3 splice form profile had a significant association with nocturnal energy expenditure, independently of effects of weight. For a subset of the Tnnt3 splice forms, obese Zucker rats failed to make the same adjustments; that is, they did not show the same relationship between body weight and the relative abundance of five Tnnt3 b splice forms (i.e. Tnnt3 b2-b5 and b8), four of which showed significant effects on nocturnal energy expenditure in Sprague-Dawley rats. Heavier obese Zucker rats displayed certain splice form relative abundances (e.g. Tnnt3 b3) characteristic of much lighter, lean animals, resulting in a mismatch between body weight and muscle molecular composition. Consequently, we suggest that body weight-inappropriate skeletal muscle Tnnt3 expression in obesity is a candidate mechanism for muscle weakness and reduced mobility. Weightdependent quantitative variation in Tnnt3 alternative splicing appears to be an evolutionarily conserved feature of skeletal muscle and provides a quantitative molecular marker to track how an animal perceives and responds to body weight. Supplementary material available online at

Section: Introductionsupporting

confidence: 79%

Body weight-dependent troponin T alternative splicing is evolutionarily conserved from insects to mammals and is partially impaired in skeletal muscle of obese rats

Schilder

Kimball

Journal of Experimental Biology

et al. 2011

“…There is nearly as strong a correlation between the summed relative abundance of the same two transcripts and the power output of intact muscle (Figure 3d). Experiments in other animals have repeatedly shown that manipulation of Tnt genes and/or protein isoforms affects muscle calcium sensitivity and contractile performance (Ogut et al, 1999;Gomes et al, 2002Gomes et al, , 2004MacFarland et al, 2002;Nassar et al, 2005;Brotto et al, 2006;Chandra et al, 2006), and single amino-acid replacement mutations in human Tnt also have these effects (Hernandez et al, 2005).…”

Section: As and The Generation Of Plastic Organism-level Phenotypesmentioning

confidence: 99%

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

2006

Heredity

Alternative splicing (AS) of pre-messenger RNA is a common phenomenon that creates different transcripts from a single gene, and these alternative transcripts affect phenotypes. The majority of AS research has examined tissue and developmental specificity of expression of particular AS transcripts, how this specificity affects cell function, and how aberrant AS is related to disease. Few studies have examined quantitative between-individual variation in AS within a cell or tissue type, or in relation to phenotypes, but the results are compelling: quantitative variation in AS affects plastic traits such as stress, anxiety, fear, egg production, muscle performance, energetics and plant growth. Genomic analyses of AS are also at a nascent stage, but have revealed a number of significant evolutionary patterns. Growing knowledge of upstream genes and kinases that regulate AS provides the as-yet little explored potential to examine how these genes and pathways respond to environmental and genotype variables. Research in this area can provide glimpses of a labyrinth of genetic architectures that have rarely been considered in evolutionary and organismal biology, or in quantitative genetics. The scarcity of contribution to knowledge about AS from these fields is illustrated by the fact that heritability of quantitative variation in AS has not yet been determined for any gene in any organism. New research tactics that incorporate quantitative analyses of AS will allow organismal and evolutionary biologists to attain a fuller mechanistic understanding of many of the traits they study, and may lead to more rapid discovery of functionally important polymorphisms.

“…In all animal species examined to date, Tnt undergoes alternative splicing (AS) to form multiple protein isoforms that differ in their amino acid sequence and function. Experiments with vertebrate striated muscle have consistently shown that manipulation of Tnt isoform content affects muscle calcium sensitivity and contractile performance (Ogut et al, 1999;Gomes et al, 2002;MacFarland et al, 2002;Gomes et al, 2004;Nassar et al, 2005;Brotto et al, 2006;Chandra et al, 2006). Single amino acid replacement mutations in human Tnt have similar effects (Hernandez et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Weight and nutrition affect pre-mRNA splicing of a muscle gene associated with performance, energetics and life history

Journal of Experimental Biology

Fescemyer

Saastamoinen

et al. 2008

SUMMARYA fundamental feature of gene expression in multicellular organisms is the production of distinct transcripts from single genes by alternative splicing (AS), which amplifies protein and functional diversity. In spite of the likely consequences for organismal biology, little is known about how AS varies among individuals or responds to body condition, environmental variation or extracellular signals in general. Here we show that evolutionarily conserved AS of troponin-t in flight muscle of adult moths responds in a quantitative fashion to experimental manipulation of larval nutrition and adult body weight. Troponin-t (Tnt) isoform composition is known to affect muscle force and power output in other animals, and is shown here to be associated with the thorax mass-specific rate of energy consumption during flight. Loading of adults with external weights for 5 days caused an AS response nearly identical to equal increases in actual body weight. In addition, there were effects of larval feeding history on adult Tnt isoform composition that were independent of body weight, with moths from poorer larval feeding regimes producing isoform profiles associated with reduced muscle performance and energy consumption rate. Thus, Tnt isoform composition in striated muscle is responsive to both weight-sensing and nutrition-sensing mechanisms, with consequent effects on function. In freeliving butterflies, Tnt isoform composition was also associated with activity level and very strongly with the rate of egg production. Overall, these results show that AS of a muscle gene responds in a quantitative fashion to whole-organism variables, which apparently serves to coordinate muscle strength and energy expenditure with body condition and life history.