Critical roles for α/ß hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond.

Mutations in the gene encoding comparative gene identification 58 (CGI-58), also known as α ß hydrolase domain-containing 5 (ABHD5), cause neutral lipid storage disorder with ichthyosis (NLSDI). This inborn error in metabolism is characterized by ectopic accumulation of triacylglycerols (TAG) within cytoplasmic lipid droplets in multiple cell types. Studies over the past decade have clearly demonstrated that CGI-58 is a potent regulator of TAG hydrolysis in the disease-relevant cell types. However, despite the reproducible genetic link between CGI-58 mutations and TAG storage, the molecular mechanisms by which CGI-58 regulates TAG hydrolysis are still incompletely understood. It is clear that CGI-58 can regulate TAG hydrolysis by activating the major TAG hydrolase adipose triglyceride lipase (ATGL), yet CGI-58 can also regulate lipid metabolism via mechanisms that do not involve ATGL. This review highlights recent progress made in defining the physiologic and biochemical function of CGI-58, and its broader role in energy homeostasis. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.

The effect of exercise hypertrophy and disuse atrophy on muscle contractile properties: a mechanomyographic analysis.

PURPOSE: To determine whether mechanomyographic (MMG) determined contractile properties of the biceps brachii change during exercise-induced hypertrophy and subsequent disuse atrophy. METHODS: Healthy subjects (mean ± SD, 23.7 ± 2.6 years, BMI 21.8 ± 2.4, n = 19) performed unilateral biceps curls (9 sets × 12 repetitions, 5 sessions per week) for 8 weeks (hypertrophic phase) before ceasing exercise (atrophic phase) for the following 8 weeks (non-dominant limb; treatment, dominant limb; control). MMG measures of muscle contractile properties (contraction time; T c, maximum displacement; D max, contraction velocity; V c), electromyographic (EMG) measures of muscle fatigue (median power frequency; MPF), strength measures (maximum voluntary contraction; MVC) and measures of muscle thickness (ultrasound) were obtained. RESULTS: Two-way repeated measures ANOVA showed significant differences (P < 0.05) between treatment and control limbs. During the hypertrophic phase treatment MVC initially declined (weeks 1-3), due to fatigue (decline in MPF), followed by improvement against control during weeks 6-8. Between weeks 5 and 8 treatment, muscle thickness was greater than control, reflecting gross hypertrophy. MMG variables Dmax (weeks 2, 7) and Vc (weeks 7, 8) declined. During the atrophic phase, MVC (weeks 9-12) and muscle thickness (weeks 9, 10) initially remained high before declining to control levels, reflecting gross atrophy. MMG variables D max (weeks 9, 14) and V c (weeks 9, 14, 15) also declined during the atrophic phase. No change in T c was found throughout the hypertrophic or atrophic phases. CONCLUSIONS: MMG detects changes in contractile properties during stages of exercise-induced hypertrophy and disuse atrophy suggesting its applicability as a clinical tool in musculoskeletal rehabilitation.

Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

The architecture and contraction time of intrinsic foot muscles.

Although critical for effective human locomotion and posture, little data exists regarding the segmentation, architecture and contraction time of the human intrinsic foot muscles. To address this issue, the Abductor Hallucis (AH), Abductor Digiti Minimi (ADM), Flexor Digitorum Brevis (FDB) and Extensor Digitorum Brevis (EDB) were investigated utilizing a cadaveric dissection and a non-invasive whole muscle mechanomyographic (wMMG) technique. The segmental structure and architecture of formaldehyde-fixed foot specimens were determined in nine cadavers aged 60-80 years. The wMMG technique was used to determine the contraction time (Tc) of individual muscle segments, within each intrinsic foot muscle, in 12 volunteers of both genders aged between 19 and 24 years. While the pattern of segmentation and segmental -architecture (e.g. fibre length) and -Tc of individual muscle segments within the same muscle were similar, they varied between muscles. Also, the average whole muscle Tc of FDB was significantly (p < 0.05) shorter (faster) (Tc = 58 ms) than in all other foot muscles investigated (ADM Tc = 72 ms, EDB Tc = 72 ms and ABH Tc = 69 ms). The results suggest that the architecture and contraction time of the FDB reflect its unique direct contribution, through toe flexion, to postural stability and the rapid development of ground reaction forces during forceful activities such as running and jumping.