Attenuated PGC-1α Isoforms following Endurance Exercise with Blood Flow Restriction.

INTRODUCTION: Exercise performed with blood flow restriction simultaneously enhances the acute responses to both myogenic and mitochondrial pathways with roles in training adaptation. We investigated isoform-specific gene expression of the peroxisome proliferator-activated receptor gamma coactivator 1 and selected target genes and proteins regulating skeletal muscle training adaptation. METHODS: Nine healthy, untrained males participated in a randomized, counterbalanced, crossover design in which each subject completed a bout of low-intensity endurance exercise performed with blood flow restriction (15 min cycling at 40% of V˙O2peak, BFR-EE), endurance exercise (30 min cycling at 70% of V˙O2peak, EE), or resistance exercise (4 × 10 repetitions of leg press at 70% of one-repetition maximum) separated by at least 1 wk of recovery. A single resting muscle biopsy (vastus lateralis) was obtained 2 wk before the first exercise trial (rest) and 3 h after each bout. RESULTS: Total PGC-1α mRNA abundance, along with all four isoforms, increased above rest with EE only (P < 0.05) being higher than BFR-EE (P < 0.05). PGC-1α1, 2, and 4 were higher after EE compared with resistance exercise (P < 0.05). EE also increased vascular endothelial growth factor, Hif-1α, and MuRF-1 mRNA abundance above rest (P < 0.05), whereas COXIV mRNA expression increased with EE compared with BFR-EE (P < 0.05). CONCLUSION: The attenuated expression of all four PGC-1α isoforms when EE is performed with blood flow restriction suggests this type of exercise provides an insufficient stimulus to activate the signaling pathways governing mitochondrial and angiogenesis responses observed with moderate- to high-intensity EE.

A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function.

Activation of brown and beige fat can reduce obesity and improve glucose homeostasis through nonshivering thermogenesis. Whether brown or beige fat also secretes paracrine or endocrine factors to promote and amplify adaptive thermogenesis is not fully explored. Here we identify Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells. In isolated cells and in mice, full-length Slit2 is cleaved to generate several smaller fragments, and we identify an active thermogenic moiety as the C-terminal fragment. This Slit2-C fragment of 50 kDa promotes adipose thermogenesis, augments energy expenditure, and improves glucose homeostasis in vivo. Mechanistically, Slit2 induces a robust activation of PKA signaling, which is required for its prothermogenic activity. Our findings establish a previously unknown peripheral role for Slit2 as a beige fat secreted factor that has therapeutic potential for the treatment of obesity and related metabolic disorders.

Lamin A/C depletion enhances DNA damage-induced stalled replication fork arrest.

The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this impacts the mechanisms that maintain genomic stability is unclear. Here, we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX focus formation but a higher frequency of cells with delayed γ-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea-induced replication stress, lamin A/C-deficient cells had an increased frequency of cells with delayed disappearance of γ-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data can be interpreted to suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair.