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High througuput sequencing of skeletal muscle-specific Site-1 Protease knockout mouse gastrocnemius and soleus

ABSTRACT: The processes by which mitochondria respond to cellular energy demands brought on by physiologic and pathophysiologic stimuli are essential to cellular adaptation and organismal survival. Disrupted mitochondrial function is implicated in several human disease states, underscoring the need to elucidate the molecular mechanisms that control mitochondrial function and metabolism. We previously described a patient with a gain-of-function mutation in Site-1 Protease (S1P) who exhibited idiopathic hyperCKemia, myoedema, and altered muscle mitochondrial morphology. To date, S1P has been heavily characterized in liver and bone, with very little known about its potential function in skeletal muscle. In our current study, we generated a skeletal muscle-specific S1P knockout mouse line (S1PsmKO) to examine the role of S1P in skeletal muscle. S1PsmKO mice were overtly normal in their appearance and health. However, examination of 12-week-old S1PsmKO mice showed increased gastrocnemius muscle mass and aged S1PsmKO mice exhibited increased muscle mass in both gastrocnemius and soleus relative to age-matched controls. Moreover, isolated muscle from S1PsmKO exhibited increased maximal mitochondrial respiration relative to floxed littermates (controls). RNA-Seq analysis showed increased transcript numbers of the mitochondrial-resident gene, Mss51 in S1PsmKO gastrocnemius relative to control mice. Mss51 is a member of the TGF-β/MSTN pathway, which controls mitochondrial metabolism. Similar to S1PsmKO muscle, S1P-depleted C2C12 cells also had increased maximal respiration, which was reversed by exogenous MSS51 expression. These data identify S1P as a regulator of muscle mass and mitochondrial metabolism, and implicate S1P as a novel modulator of TGF-β signaling. Method: Male mice were maintained on standard chow diet until 12 weeks of age.

ORGANISM(S): Mus musculus

PROVIDER: GSE199014 | GEO | 2023/04/01

REPOSITORIES: GEO

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Project description:Skeletal muscle is the largest tissue in the body and mainly relies on mitochondrial oxidative metabolism for sustainable ATP production. Reduced oxygen availability, also known as hypoxia, can be caused by high altitude or pathology and impacts mitochondria. Whereas long-term hypoxia results in increased reliance on glycolysis, reduced fatty acid oxidation and a decreased skeletal muscle mass, the in vivo mechanisms of adaptation of skeletal muscle to acute hypoxia remain elusive. Therefore, we aimed to provide an integrated description of the response of the M. gastrocnemius to acute hypoxia. Fasted male C57BL/6JOlaHsd mice were exposed to 12% oxygen representing normobaric hypoxia versus 21% oxygen (normoxia) for six hours (n=12 mice per group). Whole-body energy metabolism and the transcriptome response of the M. gastrocnemius mice was analyzed and confirmed by acylcarnitine determination and RT-qPCR. On whole-body level, six hours of hypoxia reduced energy expenditure, increased blood glucose and tended to further decrease the respiratory exchange ratio (RER). Whole genome transcriptome analysis revealed upregulation of the FOXO signalling pathway including an increased expression of Trib3, which was positively correlated with blood glucose. Apart from upregulation of Cpt1a, which negatively correlated with the RER, and SLC25a25 (Cact), fatty acid β-oxidation was not regulated. Together with significantly increased muscle C14 and C16-acylcarnitines this supports no increased fatty acid catabolism in muscle. In addition, the hypoxia-induced FOXO activation could also be connected to altered gene profiles related to fiber type switching, extracellular matrix remodelling, muscle differentiation and the denervation of neuromuscular junctions (NMJ). Conclusively, our results suggest that an acute, six hours exposure of mice to hypoxia impacts M. gastrocnemius via FOXO1, initiating alterations in skeletal muscle that may ultimately contribute to tissue remodelling. This supports an early role of hypoxia in tissue alterations in hypoxia-associated conditions such as aging and obesity. The observed impact of hypoxia on denervated NMJ is novel and warrants further investigation.

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High througuput sequencing of skeletal muscle-specific Site-1 Protease knockout mouse gastrocnemius and soleus

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