Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p = 4 × 10⁻¹⁷), arthritis (GDF5p = 4 × 10⁻¹³), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Objective: Skeletal muscle fat infiltration (known as myosteatosis) is greater in African compared with European ancestry men and may play an important role in the development of type 2 diabetes (T2D). However, prospective studies examining the magnitude of changes in myosteatosis with aging and their metabolic consequences are sparse.Methods: Longitudinal changes in peripheral quantitative computed tomography measured calf myosteatosis [intermuscular fat (mm²) and skeletal muscle density as a measure of intramuscular fat (mg/cm³)] were examined in 1515 Afro‐Caribbean men aged 40+ years recruited without regard to their health status.Results: During an average of 6.2 years of follow‐up, an age‐related increase in intermuscular fat and a decrease in skeletal muscle density were observed (all P < 0.0001), which remained significant in those who lost weight, gained weight, or remained weight stable (all P < 0.0001). In addition, muscle density loss accelerated with increasing age (P < 0.0001). Increased intermuscular fat during follow‐up was associated with an increased incident risk of T2D independent of factors known to be associated with T2D (odds ratios per 1‐SD increase in intermuscular fat = 1.29; 95% CI = 1.08‐1.53).Conclusions: Our findings suggest that both inter‐ and intramuscular fat increase with advancing age and that intermuscular fat contributes to development of T2D among African ancestry men.

Emerging evidence indicates that ectopic skeletal muscle adiposity may be a novel risk factor for type 2 diabetes (T2D), especially in African ancestry individuals. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf related protein 1 (DKK1), plays a role in adiposity regulation and could be a novel biomarker for adiposity in humans. The objective of this study was to test if serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 African ancestry men aged 40+ years (mean age 63.5 ± 8.2 yrs, mean BMI 27.8 ± 4.5 kg/m²). Anthropometrics included DXA measured total body and trunk adiposity, and CT measured lower leg skeletal muscle density (which reflects the intra-muscular adiposity content (mg/cm³)). Serum DKK1 was positively correlated with BMI (r=0.20, p=0.01), waist circumference (r=0.15, p=0.046), DXA total body adiposity (r=0.24, p=0.003), and DXA trunk adiposity (r=0.21, p=0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r= -0.25, p=0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels, or HOMA-IR. These findings suggest for the first time that higher levels of serum DKK1 may be associated with greater overall, central and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

Background: Adipose tissue (AT) around and within non-AT organs (i.e., ectopic adiposity) is emerging as a strong risk factor for type 2 diabetes (T2D). Not known is whether major ectopic adiposity depots, such as hepatic, skeletal muscle, and pericardial adiposity (PAT), are associated with T2D independent of visceral adiposity (VAT). More data are particularly needed among high-risk nonobese minority populations, as the race/ethnic gap in T2D risk is greatest among nonobese. Methods: Thus, we measured several ectopic adiposity depots by computed tomography in 718 (mean age = 64 years) African-Caribbean men on the Island of Tobago overall, and stratified by obesity (obese N = 187 and nonobese N = 532). Results: In age, lifestyle risk factors, health status, lipid-lowering medication intake, body mass index and all other adiposity-adjusted regression analyses, and hepatic and skeletal muscle adiposity were associated with T2D among nonobese men only (all P < 0.05), despite no association between VAT and PAT and T2D. Conclusions: Our results support the “ectopic fat syndrome” theory in the pathogenesis of T2D among nonobese African-Caribbean men. Longitudinal studies are needed to clarify the independent role of ectopic adiposity in T2D, and to identify possible biological mechanisms underlying this relationship, particularly in high-risk African ancestry and other nonwhite populations.

Circulating levels of procollagen type III N-terminal peptide (P3NP) may reflect increased fibrosis of skeletal muscle and other tissues with aging. Herein, we tested if P3NP was associated with baseline and 7-year change in physical function. Participants (n = 400) were from the Long Life Family Study, a study of exceptional familial longevity. Plasma P3NP concentration was measured using a sandwich enzyme-linked immunosorbent assay (inter-assay coefficient of variation <5.5%). At baseline and 7-year follow-up visits, physical function was measured using the Short Physical Performance Battery (SPPB score 0–12), which consists of gait speed, balance, and chair-rise tests. Grip strength was measured using a handheld dynamometer. The association between log-transformed P3NP and physical function was examined using generalized estimating equations adjusted for familial relatedness, age, sex, height, weight, lifestyle characteristics, liver function, kidney function, lung function, and chronic disease prevalence. Participants were aged 73.1 ± 15.2 years (range: 39–104), 54% female, had body mass index of 26.6 ± 4.3 kg/m², and gait speeds of 1.0 ± 0.3 m/s. One standard deviation higher log-transformed P3NP was related to worse baseline SPPB score (β = −0.9_points), gait speed (β = −0.05_m/s), chair-rises per-second (β = −0.46_{chair-rises/10 seconds}), and grip strength (β = −2.0_kg; all p < .001). Higher P3NP was also associated with greater declines in gait speed (β = −1.41, p < .001) and transitioning to being unable to perform chair-rises (β = 0.41, p < .001) after 7 years. Plasma P3NP may be a strong, novel biomarker of current and future physical function. Future research is needed to extend our findings to other cohorts and determine mechanisms underlying these associations.

Background: Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years). Methods and Results: Gene expression was assessed using a custom Nanostring nC ounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial‐ankle pulse‐wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse‐wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway ( APC ), glycogen synthase kinase 3β ( GSK 3B ), and transcription factor 4 ( TCF 4 ) were significantly associated with arterial stiffness ( P <0.05 for all). When entered into a single model, APC and TCF 4 expression remained independently associated with arterial stiffness ( P =0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse‐wave velocity. Conclusions: The current study establishes a novel association between in vivo expression of the Wnt pathway genes, APC and TCF 4 , with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.