The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle

Regulation of the genome is viewed through the prism of gene expression, DNA replication and DNA repair as controlled through transcription, chromatin compartmentalisation and recruitment of repair factors by enzymes such as DNA polymerases, ligases, acetylases, methylases and cyclin-dependent kinases. However, recent advances in the field of muscle cell physiology have also shown a compelling role for ‘outside-in’ biophysical control of genomic material through mechanotransduction. The crucial hub that transduces these biophysical signals is called the Linker of Nucleoskeleton and Cytoskeleton (LINC). This complex is embedded across the nuclear envelope, which separates the nucleus from the cytoplasm. How the LINC complex operates to mechanically regulate the many functions of DNA is becoming increasingly clear, and recent advances have provided exciting insight into how this occurs in cells from mechanically activated tissues such as skeletal and cardiac muscle. Nevertheless, there are still some notable shortcomings in our understanding of these processes and resolving these will likely help us understand how muscle diseases manifest at the level of the genome

The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle

Regulation of the genome is viewed through the prism of gene expression, DNA replication and DNA repair as controlled through transcription, chromatin compartmentalisation and recruitment of repair factors by enzymes such as DNA polymerases, ligases, acetylases, methylases and cyclin-dependent kinases. However, recent advances in the field of muscle cell physiology have also shown a compelling role for ‘outside-in’ biophysical control of genomic material through mechanotransduction. The crucial hub that transduces these biophysical signals is called the Linker of Nucleoskeleton and Cytoskeleton (LINC). This complex is embedded across the nuclear envelope, which separates the nucleus from the cytoplasm. How the LINC complex operates to mechanically regulate the many functions of DNA is becoming increasingly clear, and recent advances have provided exciting insight into how this occurs in cells from mechanically activated tissues such as skeletal and cardiac muscle. Nevertheless, there are still some notable shortcomings in our understanding of these processes and resolving these will likely help us understand how muscle diseases manifest at the level of the genome

Significance of predicted future liver remnant volume on liver failure risk after major hepatectomy: a case matched comparative study

IntroductionFuture liver remnant volume (FLRV), a risk factor for liver failure (PHLF) after major hepatectomy (MH), is not routinely measured. This study aimed to evaluate the association between FLRV and PHLF.Patients and methodsAll patients undergoing MH (4 + segments) between 2011 and 2018 were identified from a prospectively maintained single-centre database. Perioperative data were collected for patients with PHLF, who were matched (1:2) with non-PHLF controls. FLRV and FLRV% (i.e., % of total liver volume) were calculated retrospectively from preoperative CT scans using Synapse-3D software, and compared between the PHLF and matched control groups.ResultsOf 711 patients undergoing MH, PHLF occurred in 27 (3.8%), of whom 24 had preoperative CT scans available. These patients were matched to 48 non-PHLF controls, 98% of whom were classified as being at high risk of PHLF on preoperative risk scoring. FLRV% was significantly lower in the PHLF group, compared to matched controls (median: 28.7 vs. 35.2%, p = 0.010), with FLRV% < 30% in 58% and 29% of patients, respectively. Assessment of the ability of FLRV% to differentiate between PHLF and matched controls returned an area under the ROC curve of 0.69, and an optimal cut-off value of FLRV% < 31.5%, which yielded 79% sensitivity and 67% specificity.ConclusionsFLRV% is significantly predictive of PHLF after MH, with over half of patients with PHLF having FLRV% < 30%. In light of this, we propose that all patients should undergo risk stratification prior to MH, with the high risk patients additionally being assessed with CT volumetry

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease