Involvement of adiponectin in the pathogenesis of dystrophinopathy

Abstract

Background: The hormone adiponectin (ApN) is decreased in the metabolic syndrome, where it plays a key pathogenic role. ApN also exerts some anti-inflammatory effects on skeletal muscles in mice exposed to acute or chronic inflammation. Here, we investigate whether ApN could be sufficiently potent to counteract a severe degenerative muscle disease, with an inflammatory component such as Duchenne muscular dystrophy (DMD). Methods: Mdx mice (a DMD model caused by dystrophin mutation) were crossed with mice overexpressing ApN in order to generate mdx-ApN mice; only littermates were used. Different markers of inflammation/oxidative stress and components of signaling pathways were studied. Global force was assessed by in vivo functional tests, and muscle injury with Evans Blue Dye (EBD). Eventually, primary cultures of human myotubes were used.

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

“…One microgram of total RNA was reverse transcripted using RevertAid H Minus First-Strand cDNA Synthesis Kit (Thermo Scientific). RT-qPCR primers for human Tata box-binding protein (TBP), ApN, TNFα, IL-6, and Utrophin A (UTRN A) were similar to those previously reported [18, 23]. The other primer sequences were IL-17A (sense, 5′-AACGCTGATGGGAACGTGGA-3′; antisense, 5′-GCAGCCCACGGACACCAGTA-3′), CCL28 (sense, 5′-GGATTGTGACTTGGCTGCTGTC-3′; antisense, 5′-CCATGGTGTTTCTTCCTGTGGC-3′) MyoD (sense, 5′-CTGCTCCTTTGCCACAACG-3′; antisense, 5′-GAGTCGAAACACGGGTCGTC-3′), Myogenin (sense, 5′-ACTTCTACCAGGAACCCCGCT-3′; antisense, 5′-GGACAGGCAGGTAGTTTTCCC-3′), Mrf4 (sense, 5′-TAACGGCTAAGGAAGGAGGAGC-3′; antisense, 5′-CAAGCGCAGGCTCAGTTACTTC-3′), AdipoR1 (sense, 5′-ACTCCTAAGCACCGGCAGAC-3′; antisense, 5′-CAAGCCAAGTCCCAGGAACA-3′), SIRT1 (sense, 5′-AACAGGTTGCGGGAATCCAAAG-3′; antisense, 5′-GGCACCTAGGACATCGAGGAAC-3′) and PGC-1α (sense, 5′-TTGACTGGCGTCATTCAGGAGC-3′; antisense, 5′-AGGAAGATCTGGGCAAGAGGC-3′).…”

“…The pathway including AMPK, a deacetylase, Sirtuin (SIRT) 1, and the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is required for the beneficial effects of ApN on the skeletal muscle [17, 18]. …”

“…Moreover, we showed that mdx transgenic mice overexpressing ApN exhibited higher global muscular force and endurance along with decreased muscle damage [18]. The aims of this work were (1) to test whether ApN affords similar anti-inflammatory properties in human dystrophic myotubes, (2) to identify novel myokines targeted by ApN in these DMD myotubes, and (3) to unravel the more proximal events underlying the anti-inflammatory effects of ApN.…”

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

“…Mice with muscle-specific disruption of AdipoR1 also exhibited a local decrease in oxidative-stress-detoxifying enzymes [11]. Moreover, ApN disclosed strong anti-inflammatory properties in human myotubes when submitted to an inflammatory challenge [56,57]. ApN could also put a brake on local inflammation by functioning as a direct regulator of macrophage phenotype favoring the switch from a pro-inflammatory M1-like state to an anti-inflammatory M2-like state, as shown in vivo and in vitro [58].…”

“…Mechanistically, the anti-inflammatory effects of ApN in human "healthy" myotubes were linked to activation of the AdipoR1-AMPK-SIRT1-PGC-1α pathway [56,57]. The AMPK pathway is known to inhibit inflammation and oxidative stress by repressing the activity of the transcription factor, nuclear factor kappa B (NF-κB), a key inducer of inflammatory responses [59].…”