7 research outputs found

    Systemic down-regulation of delta-9 desaturase promotes muscle oxidative metabolism and accelerates muscle function recovery following nerve injury.

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    The progressive deterioration of the neuromuscular axis is typically observed in degenerative conditions of the lower motor neurons, such as amyotrophic lateral sclerosis (ALS). Neurodegeneration in this disease is associated with systemic metabolic perturbations, including hypermetabolism and dyslipidemia. Our previous gene profiling studies on ALS muscle revealed down-regulation of delta-9 desaturase, or SCD1, which is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Interestingly, knocking out SCD1 gene is known to induce hypermetabolism and stimulate fatty acid beta-oxidation. Here we investigated whether SCD1 deficiency can affect muscle function and its restoration in response to injury. The genetic ablation of SCD1 was not detrimental per se to muscle function. On the contrary, muscles in SCD1 knockout mice shifted toward a more oxidative metabolism, and enhanced the expression of synaptic genes. Repressing SCD1 expression or reducing SCD-dependent enzymatic activity accelerated the recovery of muscle function after inducing sciatic nerve crush. Overall, these findings provide evidence for a new role of SCD1 in modulating the restorative potential of skeletal muscles

    SCD1 expression in ALS patient muscle and after nerve injury.

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    <p>(A) Expression of SCD1 and SCD5 in deltoid muscle biopsies from ALS patients and healthy subjects (CT, white columns), as identified by microarray analysis of the database deposited at <a href="http://www.ebi.ac.uk/arrayexpress/(accession" target="_blank">http://www.ebi.ac.uk/arrayexpress/(accession</a> number E-MEXP-3260) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064525#pone.0064525-Pradat1" target="_blank">[12]</a>. ALS samples were obtained from muscle not clinically or electromyography affected (Unaff, orange columns) and from muscle with advanced pathology, characterized by reduced strength and neurogenic electromyography pattern (Aff, brown columns). *<i>P</i><0.05 (1-way ANOVA followed by Tukey's multiple comparison test, n = 4–10). (B) Expression of SCD1 in gastrocnemius following sciatic nerve axotomy (Axo) or crush at indicated post-operation days. Contralateral muscle expression is represented by 100% baseline. **<i>P</i><0.01, ***<i>P</i><0.001 (One sample t-test, n = 4–10).</p

    Gene expression specific to the motor end plate in SCD1 knockout mice.

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    <p>Expression of AChR-α, AChR-Îł, AChR-Δ and MuSK in gastrocnemius and tibialis anterior from SCD1 knockout mice (brown columns) and wild-type littermates (white columns). *<i>P</i><0.05, ***<i>P</i><0.001 (Unpaired t-test, n = 4–11).</p

    Muscle function recovery in SCD-deficient mice submitted to nerve crush.

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    <p>Restoration of muscle grip strength in SCD1 knockout mice (A) or MF-438 treated mice (C) (black circles) and corresponding control littermates (white circles) at the indicated post-operation times. ***<i>P</i><0.001 (2-way ANOVA, n = 4–12). Percentage of electromyography episodes of spontaneous activity in SCD1 knockout mice (Inset A) or MF-438 treated mice (Inset C) (KO or MF, brown columns) and corresponding control littermates (WT or CT, white columns) two weeks after sciatic nerve crush. *<i>P</i><0.05 (Unpaired t-test, n = 4–7). (B) Relative density of muscle fiber types in ipsilateral and contralateral tibialis anterior from SCD1 knockout mice and wild-type littermates two weeks after sciatic nerve crush. According to SDH histochemistry, fibers were classified as dark brown colored fibers with high metabolic oxidative capacity (brown columns), pale brown colored fibers with medium oxidative capacity (orange columns) and non-satined fibers (white columns). *<i>P</i><0.05 and ***<i>P</i><0.001 (1-way ANOVA followed by Tukey's multiple comparison test, (n = 4–6). (D) Kaplan-Meier curves showing the percentage of MF-438 treated mice (black circles) and control littermates (white circles) that started to exhibit a grip strength distinct from zero after initial total paralysis. Logrank test (n = 10–11). Inset D, averaged time at start of recovery in MF-438 treated mice (MF, brown column) and control littermates (CT, white column). *<i>P</i><0.05 (Unpaired t-test, n = 10–11).</p

    Effects of MF-438 on metabolism and muscle function.

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    <p>(A) C16:1/C16:0 and C18:1/C18:0 fatty acid ratio in plasma from MF-438 treated mice (brown columns) and control littermates (CT, white columns). ***<i>P</i><0.001 (Unpaired t-test, n = 4–6). (B) Time course of respiratory quotient (RQ) before and after treatment with MF-438 at a dose of 10 mg/kg body mass/day (indicated by the black bar) (n = 4). Time course of body mass (C), muscle grip strength expressed as a percentage of day 0 (D), and specific grip strength, as determined by normalizing peak force to body mass (E), in mice fed regular chow (white circles) and mice fed regular chow supplemented with MF-438 (black circles). **<i>P</i><0.01 (2-way ANOVA followed by Bonferroni test, n = 5–6). (F) Expression of PGC1-α, AChR-α, and MuSK in gastrocnemius from MF-438 treated mice (brown columns) and control littermates (white columns). *<i>P</i><0.05 (Unpaired t-test, n = 3–9).</p

    Metabolic phenotype of muscle from SCD1 knockout mice.

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    <p>(A) Expression of PGC1-α, PPARα and PDK4 in gastrocnemius and tibialis anterior from SCD1 knockout mice (brown columns) and wild-type littermates (white columns). *<i>P</i><0.05, **<i>P</i><0.01 (Unpaired t-test, n = 3–11). (B) Number of muscle fibers in tibialis anterior from SCD1 knockout mice (KO, brown column) and wild-type littermates (WT, white column). *<i>P</i><0.05 (Unpaired t-test, n = 7–10). (C) Distribution of the calibers of muscle fibers in tibialis anterior from SCD1 knockout mice (327 fibers, black circles) and wild-type littermates (283 fibers, white circles). Representative microphotographs of wild-type and knockout tibialis anterior are shown. (D) Averaged cross-sectional area of SDH-positive and SDH-negative fibers in tibialis anterior from SCD1 knockout mice (brown columns) and wild-type littermates (white columns). *<i>P</i><0.05, **<i>P</i><0.01 (Unpaired t-test, n = 7–10). (E) Number of SDH-positive (orange bars) and SDH-negative fibers (white bars) in tibialis anterior from SCD1 knockout mice (KO) and wild-type littermates (WT). ***<i>P</i><0.001 (Chi-square test, n = 283–327).</p
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