Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

BACKGROUND: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. METHODS: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). RESULTS: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. CONCLUSIONS: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.

Is hip morphology a risk factor for developing hip osteoarthritis? A systematic review with meta-analysis.

OBJECTIVE: To appraise the highest evidence on hip morphology as a risk factor for developing hip osteoarthritis (OA). DESIGN: We searched for studies evaluating the association between radiological hip morphology parameters and the prevalence, incidence or progression of hip OA (based on different radiographic and clinical criteria) in the MEDLINE, EMBASE, Web of Science, Scopus, Cochrane Library and PEDro databases from inception until June 2020. Prospective and cross-sectional studies were separately evaluated. Data are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We included 9 prospective and 21 cross-sectional studies in the meta-analysis, and evaluated 42,831 hips from 25,898 individuals (mean age: 59 years). Prospective studies showed that, compared with control hips, hips with cam morphology (alpha angle >60°; OR = 2.52, 95% CI: 1.83 to 3.46, P < 0.001) or hip dysplasia (lateral center-edge angle (LCEA) <25°; OR = 2.38, 95% CI: 1.84 to 3.07, P < 0.001), but not hips with pincer morphology (LCEA >39°; OR = 1.08, 95% CI: 0.57 to 2.07, P = 0.810), were more likely to develop hip OA than hips without these morphologies. Cross-sectional studies showed a greater prevalence of pincer morphology (LCEA >39°, OR = 3.71, 95% CI: 2.98 to 4.61, P < 0.001) and acetabular retroversion (crossover sign; OR = 2.65, 95% CI: 1.17 to 6.03, P = 0.020) in hips with OA than in control hips. CONCLUSION: Cam morphology and hip dysplasia were consistently associated with the development of hip OA. Pincer morphology was associated with hip OA in cross-sectional but not in prospective studies. The heterogeneous quantification of pincer morphology on radiographs limits a clear conclusion on its association with hip OA.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.