B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus.

OBJECTIVE: B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile. METHODS: Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases. RESULTS: Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048). CONCLUSIONS: High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.

Skeletal muscle morphology, satellite cells, and oxidative profile in relation to physical function and lifelong endurance training in very old men.

In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, including a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EAs) aged 82-92 yr, and 19 subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 yr were analyzed. ULSAM subjects were divided into high- (n = 9, HF) and low- (n = 10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome c oxidase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differences between LF and HF (P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong endurance training, but not higher physical function, was associated with higher muscle oxidative capacity, even beyond the age of 80.NEW & NOTEWORTHY Here we show that lifelong endurance training, but not physical function, is associated with higher muscle oxidative capacity, even beyond the age of 80 yr. Neither endurance training status nor physical function was significantly associated with satellite cells or markers of regeneration and denervation in muscle biopsies from these very old men.

Functional improvements to 6 months of physical activity are not related to changes in size or density of multiple lower-extremity muscles in mobility-limited older individuals.

Older adults are encouraged to engage in multicomponent physical activity, which includes aerobic and muscle-strengthening activities. The current work is an extension of the Vitality, Independence, and Vigor in the Elderly 2 (VIVE2) study - a 6-month multicenter, randomized, placebo-controlled trial of physical activity and nutritional supplementation in community dwelling 70-year-old seniors. Here, we examined whether the magnitude of changes in muscle size and quality differed between major lower-extremity muscle groups and related these changes to functional outcomes. We also examined whether daily vitamin-D-enriched protein supplementation could augment the response to structured physical activity. Forty-nine men and women (77 ± 5 yrs) performed brisk walking, muscle-strengthening exercises for the lower limbs, and balance training 3 times weekly for 6 months. Participants were randomized to daily intake of a nutritional supplement (20 g whey protein + 800 IU vitamin D), or a placebo. Muscle cross-sectional area (CSA) and radiological attenuation (RA) were assessed in 8 different muscle groups using single-slice CT scans of the hip, thigh, and calf at baseline and after the intervention. Walking speed and performance in the Short Physical Performance Battery (SPPB) were also measured. For both CSA and RA, there were muscle group × time interactions (P < 0.01). Significant increases in CSA were observed in 2 of the 8 muscles studied, namely the knee extensors (1.9%) and the hip adductors (2.8%). For RA, increases were observed in 4 of 8 muscle groups, namely the hip flexors (1.1 HU), hip adductors (0.9 HU), knee extensors (1.2 HU), and ankle dorsiflexors (0.8 HU). No additive effect of nutritional supplementation was observed. While walking speed (13%) and SPPB performance (38%) improved markedly, multivariate analysis showed that these changes were not associated with the changes in muscle CSA and RA after the intervention. We conclude that this type of multicomponent physical activity program results in significant improvements in physical function despite relatively small changes in muscle size and quality of some, but not all, of the measured lower extremity muscles involved in locomotion.

Threshold-automated CT measurements of muscle size and radiological attenuation in multiple lower-extremity muscles of older individuals.

Muscle atrophy and fat infiltration, two indicators of deconditioning and weakness in elderly frail patients, are typically assessed by means of manual image analysis from computed tomography (CT) scans. As this time-consuming image analysis limits its wider use in clinical studies, the use of tissue thresholds to semi-automatically assess muscle composition has been suggested. Here, we aimed to investigate the relationship between manual and semi-automated analysis of both cross-sectional area (CSA) and radiological attenuation (RA), in multiple muscles of the lower extremities in aged (77 ± 6 years) sedentary individuals (n = 40). The participants underwent CT scans of their lower limbs, including hip, thigh and calf muscles. The subsequent analysis of CSA and RA was conducted using both manual segmentation and semi-automatic thresholds (-30 to +150 Hounsfield units). Automated measurements were generally strongly correlated with manually encircled CSA in all muscle groups (R = 0.79-0.99, p < .05) and shortened the analysis time by 70% (p < .05). In m. iliopsoas, however, the CSA became overestimated (15%, p < .05) with thresholded measurements, while the assessment of both CSA and RA was underestimated in muscles with high-fat content (i.e., the gluteal muscles) and in individuals with high-fat infiltration. In conclusion, using the semi-automated technique with conventional thresholds is a time-saving method that delivers accurate gross size of the muscle groups, particularly in the thigh. However, caution should be exercised when using semi-automated techniques for assessing CSA and fat infiltration in muscles with high-fat content.

Longitudinal Muscle and Myocellular Changes in Community-Dwelling Men Over Two Decades of Successful Aging-The ULSAM Cohort Revisited.

Participants of the population-based Uppsala longitudinal study of adult men (ULSAM) cohort reaching more than 88 years of age (survivors, S) were investigated at age 70, 82, and 88-90 and compared at 70 years with non-survivors (NS) not reaching 82 years. Body composition, muscle mass and muscle histology were remarkably stable over 18 years of advanced aging in S. Analysis of genes involved in muscle remodeling showed that S had higher mRNA levels of myogenic differentiation factors (Myogenin, MyoD), embryonic myosin (eMyHC), enzymes involved in regulated breakdown of myofibrillar proteins (Smad2, Trim32, MuRF1,) and NCAM compared with healthy adult men (n = 8). S also had higher mRNA levels of eMyHC, Smad 2, MuRF1 compared with NS. At 88 years, S expressed decreased levels of Myogenin, MyoD, eMyHC, NCAM and Smad2 towards those seen in NS at 70 years. The gene expression pattern of S at 70 years was likely beneficial since they maintained muscle fiber histology and appendicular lean body mass until advanced age. The expression pattern at 88 years may indicate a diminished muscle remodeling coherent with a decline of reinnervation capacity and/or plasticity at advanced age.