Cellular energetics of dystrophic muscle.

Revisiting the dystrophin-ATP connection: How half a century of research still implicates mitochondrial dysfunction in Duchenne Muscular Dystrophy aetiology.

Phosphorus magnetic resonance spectroscopy monitors muscle energy metabolism by recording the ratio of phosphocreatine to inorganic phosphate at rest, during exercise, and during recovery from exercise. In mitochondrial diseases, abnormalities may appear during some or all these phases. Low phosphocreatine-inorganic phosphate ratios at rest are not disease-specific, but can be increased by drug therapy in several myopathies. Phosphorus magnetic resonance spectroscopy can also record intracellular pH and thus identify disorders of glycogen metabolism in which the production of lactic acid is blocked during ischemic exercise. The measurements of accumulated sugar phosphate intermediates further delineate glycolytic muscle defects. Myophosphorylase deficiency responds to intravenous glucose administration with improved exercise bioenergetics, but no such response is seen in phosphofructokinase deficiency. The muscular dystrophies show no specific bioenergetic abnormality; however, elevation of phospholipids metabolites and phosphodiesters was detected in some cases. While phosphorus magnetic resonance spectroscopy remains primarily a research tool in metabolic myopathies, it will be clinically useful in identifying new therapies and monitoring their effects in a variety of neuromuscular disorders.

Phosphorus magnetic resonance spectroscopy (31P MRS) in neuromuscular disorders.

31P nuclear magnetic resonance (NMR) was used to investigate the resting energy metabolism of the calf muscle in boys with Duchenne's muscular dystrophy. Reductions in the phosphocreatine/adenosine triphosphate (PCr/ATP) and the PCr/Pi ratios were found, but ATP as a fraction of the total mobile phosphorus signal was not reduced, and intracellular pH was normal in the Duchenne muscle. Attempts at quantitation of the NMR signal suggested that the reduced total phosphorus signal seen in the Duchenne muscle was a result of muscle fiber loss only and that the muscle fiber ATP concentration was probably normal in the diseased tissue. An exercise study in one 7-year-old boy with Duchenne's dystrophy demonstrated that the muscle had a normal ability to break down and resynthesize phosphocreatine. Presented here are the first reported trials of the effects of two putative therapeutic agents on energy metabolism determined by NMR in Duchenne's muscular dystrophy.

Muscle energy metabolism in Duchenne dystrophy studied by 31P-NMR: controlled trials show no effect of allopurinol or ribose.

Quantitative NMRI and 31P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6–18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia) and an alkaline (Pib) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2. Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78–100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2. However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy. Copyright © 2015 John Wiley & Sons, Ltd.

Quantitative NMRI and NMRS identify augmented disease progression after loss of ambulation in forearms of boys with Duchenne muscular dystrophy.

Studies of the structural and molecular features of the lymphatic vasculature, which clears fluid, macromolecules and leukocytes from the tissue microenvironment, have largely relied on animal models, with limited information in human organs beyond traditional immunohistochemical assessment. Here, we use three-dimensional imaging and single-cell RNA-sequencing to study lymphatics in the human kidney. We found a hierarchical arrangement of lymphatic vessels within human kidneys, initiating along specialised nephron epithelium in the renal cortex and displaying a distinct, kidney-specific transcriptional profile. In chronic transplant rejection we found kidney allograft lymphatic expansion alongside a loss of structural hierarchy, with human leukocyte antigen-expressing lymphatic vessels infiltrating the medulla, presenting a putative target for alloreactive antibodies. This occurred concurrently with lymphatic vessels invading and interconnecting tertiary lymphoid structures at early stages of lymphocyte colonisation. Analysis of intercellular signalling revealed upregulation of co-inhibitory molecule-mediated CD4+ T cell-lymphatic crosstalk in rejecting kidneys, potentially acting to limit local alloimmune responses. Overall, we delineate novel structural and molecular features of human kidney lymphatics and reveal perturbations to their phenotype and transcriptome in the context of alloimmunity. SUMMARY Lymphatics regulate fluid balance and immune cell accumulation but are under-studied in human organs such as the kidney. Jafree and colleagues profiled human kidney lymphatics using three-dimensional imaging and single-cell RNA-sequencing, revealing structural and transcriptional perturbations in rejecting kidney transplants.

/pdf/three-dimensional-imaging-and-single-cell-transcriptomics-of-1foz5zf9.pdf

Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity

In carrying out a new study of nucleotide concentrations in dystrophic muscle, we utilized myosin as a reference base. In nine control vastus lateralis muscle samples, nucleotide concentrations were 105 211 (SEM) moles of adenosine triphosphate (ATP) and 446 ± 57 (SEM) moles of creatine phosphate (CP) per milligram of myosin. In seven Duchenne dystrophic vastus lateralis muscle samples, nucleotide concentrations were 127 ± 25 (SEMI nmoles of ATP and 462 ± 119 (SEM) moles of CP per milligram of myosin. The CPATP ratio of 3.6 2 0.367 from Duchenne muscle was not signiificantly different from normal, 4.32 ± 0.243 (( p p p

Duchenne muscular dystrophy: adenosine triphosphate and creatine phosphate content in muscle.

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Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity

Duchenne muscular dystrophy: adenosine triphosphate and creatine phosphate content in muscle.