Shiver me titin! Elucidating titin's role in shivering thermogenesis

Taylor-Burt, Kari R; Monroy, Jenna A.; Pace, Cinnamon M.; Lindstedt, Stan L.; Nishikawa, Kiisa C.

doi:10.1242/jeb.111849

Cited by 15 publications

(29 citation statements)

References 43 publications

(62 reference statements)

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“…corroborates with myofibrils and studies across variable muscle preparations showing that mdm mutant skeletal muscles generate less contractile force than controls (Huebsch et al, 2005;Lopez et al, 2008;Monroy et al, 2012;Taylor-Burt et al, 2015). However, skinned mutant psoas fibres show only a 30% reduction in the average contractile stress compared with control fibres.…”

Section: Discussionsupporting

confidence: 84%

“…However, no increase in the stiffness of titin was observed in mutant sarcomeres, suggesting that titin-based force regulatory mechanisms are affected by the mdm mutation . Investigations of whole mdm soleus have also demonstrated active compliance of mutant soleus muscles in comparison to wild-type controls (Monroy et al, 2016;Taylor-Burt et al, 2015), further supporting the idea that titinbased force regulation is affected by the mdm mutation. From this work, we speculate that force regulatory sites are deleted from mdm titin.…”

Section: Introductionmentioning

confidence: 70%

“…Because of the large size of the titin protein, gel analyses are not sensitive enough to detect any change in size of mdm titin (Garvey et al, 2002), which may be missing more amino acids than predicted owing to aberrant post-translational processing (Lopez et al, 2008;Buck et al, 2014). Mdm mice are smaller than wild-type mice, exhibit an abnormal gait, have disrupted thermoregulation and die prematurely (Garvey et al, 2002;Huebsch et al, 2005;Monroy et al, 2016;Taylor-Burt et al, 2015). Mdm mutant muscles show muscle and fibre atrophy (Huebsch et al, 2005;Lopez et al, 2008;Monroy et al, 2016;Taylor-Burt et al, 2015), increased satellite cell populations (Heimann et al, 1996), increased occurrence of centralized nuclei (Heimann et al, 1996;Lopez et al, 2008) and large connective tissue deposits (Lopez et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Mdm mice are smaller than wild-type mice, exhibit an abnormal gait, have disrupted thermoregulation and die prematurely (Garvey et al, 2002;Huebsch et al, 2005;Monroy et al, 2016;Taylor-Burt et al, 2015). Mdm mutant muscles show muscle and fibre atrophy (Huebsch et al, 2005;Lopez et al, 2008;Monroy et al, 2016;Taylor-Burt et al, 2015), increased satellite cell populations (Heimann et al, 1996), increased occurrence of centralized nuclei (Heimann et al, 1996;Lopez et al, 2008) and large connective tissue deposits (Lopez et al, 2008). At the myofibril level, mutant sarcomeres are indistinguishable from healthy controls Witt et al, 2004), suggesting that the mdm mutation does not affect the structure of the sarcomeres.…”

Section: Introductionmentioning

confidence: 99%

“…At the myofibril level, mutant sarcomeres are indistinguishable from healthy controls Witt et al, 2004), suggesting that the mdm mutation does not affect the structure of the sarcomeres. Nevertheless, mechanical studies show decreased contractile force and increased passive force in mdm muscles (Huebsch et al, 2005;Lopez et al, 2008;Monroy et al, 2016;Taylor-Burt et al, 2015), suggesting that the deletion in titin and subsequent loss of titin force enhancement may influence the contractile mechanics of mdm muscles.…”

Section: Introductionmentioning

confidence: 99%

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Titin force enhancement following active stretch of skinned skeletal muscle fibres

Powers

Joumaa

Jinha

et al. 2017

Journal of Experimental Biology

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In actively stretched skeletal muscle sarcomeres, titin-based force is enhanced, increasing the stiffness of active sarcomeres. Titin force enhancement in sarcomeres is vastly reduced in mdm, a genetic mutation with a deletion in titin. Whether loss of titin force enhancement is associated with compensatory mechanisms at higher structural levels of organization, such as single fibres or entire muscles, is unclear. The aim of this study was to determine whether mechanical deficiencies in titin force enhancement are also observed at the fibre level, and whether mechanisms compensate for the loss of titin force enhancement. Single skinned fibres from control and mutant mice were stretched actively and passively beyond filament overlap to observe titin-based force. Mutant fibres generated lower contractile stress (force divided by cross-sectional area) than control fibres. Titin force enhancement was observed in control fibres stretched beyond filament overlap, but was overshadowed in mutant fibres by an abundance of collagen and high variability in mechanics. However, titin force enhancement could be measured in all control fibres and most mutant fibres following short stretches, accounting for ∼25% of the total stress following active stretch. Our results show that the partial loss of titin force enhancement in myofibrils is not preserved in all mutant fibres and this mutation likely affects fibres differentially within a muscle. An increase in collagen helps to reestablish total force at long sarcomere lengths with the loss in titin force enhancement in some mutant fibres, increasing the overall strength of mutant fibres.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Titin force enhancement following active stretch of skinned skeletal muscle fibres

Powers

Joumaa

Jinha

et al. 2017

Journal of Experimental Biology

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The effects of a skeletal muscle titin mutation on walking in mice

et al. 2016

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Titin contributes to sarcomere assembly, muscle signaling, and mechanical properties of muscle. The mdm mouse exhibits a small deletion in the titin gene resulting in dystrophic mutants and phenotypically normal heterozygotes. We examined the effects of this mutation on locomotion to assess how, and if, changes to muscle phenotype explain observed locomotor differences. Mutant mice are much smaller in size than their siblings and gait abnormalities may be driven by differences in limb proportions and/or by changes to muscle phenotype caused by the titin mutation. We quantified differences in walking gait among mdm genotypes and also determined whether genotypes vary in limb morphometrics. Mice were filmed walking, and kinematic and morphological variables were measured. Mutant mice had a smaller range of motion at the ankle, shorter stride lengths, and shorter stance duration, but walked at the same relative speeds as the other genotypes. Although phenotypically similar to wildtype mice, heterozygous mice frequently exhibited intermediate gait mechanics. Morphological differences among genotypes in hindlimb proportions were small and do not explain the locomotor differences. We suggest that differences in locomotion among mdm genotypes are due to changes in muscle phenotype caused by the titin mutation.

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The genomic landscape of evolutionary convergence in mammals, birds and reptiles

Levin

2017

Nat Ecol Evol

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Many lineage-defining (nodal) mutations possess high functionality. However, differentiating adaptive nodal mutations from those that are functionally compensated remains challenging. To address this challenge, we identified functional nodal mutations (fNMs) in ~3,400 nuclear DNA (nDNA) and 4 mitochondrial DNA (mtDNA) protein structures from 91 and 1,003 species, respectively, representing the entire mammalian, bird and reptile phylogeny. A screen for candidate compensatory mutations among co-occurring amino acid changes in close structural proximity revealed that such compensated fNMs encompass 37% and 27% of the mtDNA and nDNA datasets, respectively. Analysis of the remaining (non-compensated) mutations, which are enriched for adaptive mutations, showed that birds and mammals share most such recurrent fNMs (N = 51). Among the latter, we discovered mutations in thermoregulation-related genes. These represent the best candidates to explain the molecular basis of convergent body thermoregulation in birds and mammals. Our analysis reveals the landscape of possible mutational compensation and convergence in amniote phylogeny.

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Shiver me titin! Elucidating titin's role in shivering thermogenesis

Cited by 15 publications

References 43 publications

Titin force enhancement following active stretch of skinned skeletal muscle fibres

Titin force enhancement following active stretch of skinned skeletal muscle fibres

The effects of a skeletal muscle titin mutation on walking in mice

The genomic landscape of evolutionary convergence in mammals, birds and reptiles

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