title: Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy.
abstract: Weakness and fatigability are typical features of Duchenne muscular dystrophy patients and are aggravated in dystrophic mdx mice by chronic treadmill exercise. Mechanical activity modulates gene expression and muscle plasticity. Here, we investigated the outcome of 4 (T4, 8 weeks of age) and 12 (T12, 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in the gastrocnemius muscle of mdx and wild-type (WT) mice using quantitative real-time PCR. Basal expression of the exercise-sensitive genes peroxisome-proliferator receptor γ coactivator 1α (Pgc-1α) and Sirtuin1 (Sirt1) was higher in mdx versus WT mice at both ages. Exercise increased Pgc-1α expression in WT mice; Pgc-1α was downregulated by T12 exercise in mdx muscles, along with Sirt1, Pparγ and the autophagy marker Bnip3. Sixteen weeks old mdx mice showed a basal overexpression of the slow Mhc1 isoform and Serca2; T12 exercise fully contrasted this basal adaptation as well as the high expression of follistatin and myogenin. Conversely, T12 exercise was ineffective in WT mice. Damage-related genes such as gp91-phox (NADPH-oxidase2), Tgfβ, Tnfα and c-Src tyrosine kinase were overexpressed in mdx muscles and not affected by exercise. Likewise, the anti-inflammatory adiponectin was lower in T12-exercised mdx muscles. Chronic exercise with minor adaptive effects in WT muscles leads to maladaptation in mdx muscles with a disequilibrium between protective and damaging signals. Increased understanding of the pathways involved in the altered mechanical-metabolic coupling may help guide appropriate physical therapies while better addressing pharmacological interventions in translational research.
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and.
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and.
authors.forename: Maria
authors.initials: M
authors.lastname: Cannone
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari 'A. Moro', Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Giustino
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and.
authors.forename: Ada Maria
authors.initials: AM
authors.lastname: Massari
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and.
authors.forename: Roberta Francesca
authors.initials: RF
authors.lastname: Capogrosso
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and.
authors.forename: Anna
authors.initials: A
authors.lastname: Cozzoli
authors.affiliation: Unit of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari 'A. Moro', Via Orabona 4, 70125 Bari, Italy and annamaria.deluca@uniba.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008954:Models, Biological; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D013997:Time Factors