Interplay between mitochondria and reactive oxygen and nitrogen species in metabolic adaptation to hypoxia in facioscapulohumeral muscular dystrophy: potential therapeutic targets

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by descending skeletal muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4, which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms. However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics of DUX4-induced metabolic changes is lacking.Here we pinpoint the kinetic involvement of altered mitochondrial RONS metabolism and impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found elevated ROS levels correlate with increases in steady-state mitochondrial membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation prior to oxidative stress generation and apoptosis through mitochondrial ROS, and affects NO· bioavailability via mitochondrial peroxidation. We identify complex I as the primary target for DUX4-induced mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic mis-adaptation. Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial RONS metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to varying O2 tension is required.HighlightsTranscriptomics data from FSHD muscle indicates enrichment for disturbed mitochondrial pathwaysDisturbed RONS metabolism correlates with mitochondrial membrane polarisation and myotube hypotrophyDUX4-induced changes in mitochondrial function precede oxidative stress through mitoROS and affect hypoxia signalling via complex IFSHD is sensitive to environmental hypoxia, which increases ROS levels in FSHD myotubesHypotrophy in hypoxic FSHD myotubes is efficiently rescued with mitochondria-targeted antioxidantsGraphical abstract

Long-Term Environmental Hypoxia Exposure and Haematopoietic Prolyl Hydroxylase-1 Deletion Do Not Impact Experimental Crohn’s Like Ileitis

Environmental hypoxia and hypoxia-induced signalling in the gut influence inflammatory bowel disease pathogenesis, however data is limited to colitis. Hence, we investigated the effect of environmental hypoxia and immune cell-specific deletion of oxygen sensor prolyl hydroxylase (PHD) 1 in a Crohn’s like ileitis mouse model. Therefore, 5-week-old C57/BL6 TNF∆ARE/+ mice and wildtype (WT) littermates were housed in normoxia (21% O2) or hypoxia (8% O2) for 10 weeks. Systemic inflammation was assessed by haematology. Distal ileal hypoxia was evaluated by pimonidazole staining. The ileitis degree was scored on histology, characterized via qPCR and validated in haematopoietic Phd1-deficient TNF∆ARE/+ mice. Our results demonstrated that hypoxia did not impact body weight evolution in WT and TNF∆ARE/+ mice. Hypoxia increased red blood cell count, haemoglobin, haematocrit and increased pimonidazole intensity in the ileum. Interestingly, hypoxia evoked an increase in circulatory monocytes, ileal mononuclear phagocytes and proinflammatory cytokine expression in WT mice. Despite these alterations, no histological or ileal gene expression differences could be identified between TNF∆ARE/+ mice housed in hypoxia versus normoxia nor between haematopoietic Phd1-deficient TNF∆ARE/+ and their WT counterparts. Therefore, we demonstrated for the first time that long-term environmental hypoxia or haematopoietic Phd1-deletion does not impact experimental ileitis development.

Do aquatic ectotherms perform better under hypoxia after warm acclimation?

ABSTRACTAquatic animals increasingly encounter environmental hypoxia due to climate-related warming and/or eutrophication. Although acute warming typically reduces performance under hypoxia, the ability of organisms to modulate hypoxic performance via thermal acclimation is less understood. Here, we review the literature and ask whether hypoxic performance of aquatic ectotherms improves following warm acclimation. Interpretation of thermal acclimation effects is limited by reliance on data from experiments that are not designed to directly test for beneficial or detrimental effects on hypoxic performance. Most studies have tested hypoxic responses exclusively at test temperatures matching organisms' acclimation temperatures, precluding the possibility of distinguishing between acclimation and acute thermal effects. Only a few studies have applied appropriate methodology to identify beneficial thermal acclimation effects on hypoxic performance, i.e. acclimation to different temperatures prior to determining hypoxic responses at standardised test temperatures. These studies reveal that acute warming predominantly impairs hypoxic performance, whereas warm acclimation tends to be either beneficial or have no effect. If this generalises, we predict that warm-acclimated individuals in some species should outperform non-acclimated individuals under hypoxia. However, acclimation seems to only partially offset acute warming effects; therefore, aquatic ectotherms will probably display overall reduced hypoxic performance in the long term. Drawing on the appropriate methodology, future studies can quantify the ability of organisms to modulate hypoxic performance via (reversible) thermal acclimation and unravel the underlying mechanisms. Testing whether developmental acclimation and multigenerational effects allow for a more complete compensation is essential to allow us to predict species' resilience to chronically warmer, hypoxic environments.