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

Abstract

Adiponectin (ApN) is a hormone abundantly secreted by adipocytes and it is known to be tightly linked to the metabolic syndrome. It promotes insulin-sensitizing, fat-burning, and anti-atherosclerotic actions, thereby effectively counteracting several metabolic disorders, including type 2 diabetes, obesity, and cardiovascular diseases. ApN is also known today to possess powerful anti-inflammatory/oxidative and pro-myogenic effects on skeletal muscles exposed to acute or chronic inflammation and injury, mainly through AdipoR1 (ApN specific muscle receptor) and AMP-activated protein kinase (AMPK) pathway, but also via T-cadherin. In this review, we will report all the beneficial and protective properties that ApN can exert, specifically on the skeletal muscle as a target tissue. We will highlight its effects and mechanisms of action, first in healthy skeletal muscle including exercised muscle, and second in diseased muscle from a variety of pathological conditions. In the end, we will go over some of AdipoRs agonists that can be easily produced and administered, and which can greatly mimic ApN. These interesting and newly identified molecules could pave the way towards future therapeutic approaches to potentially prevent or combat not only skeletal muscle disorders but also a plethora of other diseases with sterile inflammation or metabolic dysfunction.

Keywords: AMPK; AdipoRon; Adiponectin; PGC-1α; dystrophinopathies; exercise; inflammation; insulin signaling; obesity; oxidative stress; regeneration; skeletal muscle.

Figure 1

Pleiotropic effects of adiponectin. This figure summarizes the beneficial and protective effects of ApN on a variety of tissues and organs. Green arrows represent an increase, while red arrows represent a decrease. ApN, adiponectin as globular, trimeric, hexameric or multimeric forms (starting from left symbol and going in a clockwise direction). Created with BioRender.com.

Figure 2

Adiponectin properties on healthy skeletal muscle. This figure summarizes the main metabolic effects of ApN, while specifically highlighting a central crosstalk between ApN-AdipoR1-AMPK and insulin pathways. Briefly, binding of ApN to AdipoR1 will recruit LKB1 and increase calcium influx, both required to fully activate AMPK-SIRT1-PGC-1α axis. Then, AMPK signaling will repress the activity of NF-κB and decrease muscle inflammation. It will also increase, via PGC-1α, mitochondrial biogenesis and function and favors an oxidative myofiber phenotype, while markedly decreasing oxidative stress. In addition, this pathway will limit and reduce lipid deposition via direct action, through inhibition of ACC, or indirect one, through activation of PPARα and its target genes (CPT1 and ACO). Eventually, decrease in muscle oxidative stress and lipid content, as well as inhibition of p70S6K1, will significantly reduce insulin resistance. Finally, ApN could also boost insulin sensitivity and glucose uptake by promoting IRS1 binding to insulin receptor and by activating p38MAPK, respectively. Pointed head black arrows indicate activation or induction, while blunt head red arrows indicate inhibition. Dashed and blurred circle represents removal of the indicated residue. Boxes with processes in green represent net beneficial effects of ApN, while boxes with processes in red represent metabolic dysfunctions counteracted by ApN. ApN, adiponectin. TF, transcription factors. Created with BioRender.com.

Figure 3

Pro-myogenic properties of ApN. This figure summarizes the multiple beneficial effects of ApN on several steps of muscle regeneration (boxes in green), while highlighting an important interplay among 3 major processes, including resolution of inflammation, energy metabolism, and muscle repair. These pro-myogenic properties of ApN have only been tested on rodent skeletal muscle thus far. Green arrows represent the direct pro-myogenic effects of ApN. Blue arrows represent an indirect pro-myogenic effect of ApN by inducing a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, for a resolution of inflammation and activation of the tissue-healing process. Pink arrows represent an indirect pro-myogenic effect of ApN by stimulating non-muscle stem cells and driving their commitment towards the skeletal muscle lineage. Brown arrows represent the different effects of macrophages. Created with BioRender.com.

Figure 4

Adiponectin/AdipoRon properties on diseased skeletal muscle. This figure summarizes the beneficial and protective effects of ApN and AdipoRon on dystrophic skeletal muscle, which is characterized by micro-tears in the sarcolemmal membrane due to lack of dystrophin protein. It also highlights their mechanisms of actions. Briefly, binding of either ApN or AdipoRon to AdipoR1 will activate AMPK-SIRT1-PGC-1α pathway. Then, PGC-1α represses NF-κB activity by de-phosphorylation of the p65 subunit, while SIRT1 represses it by deacetylation. This results in reduction of inflammation and an improved myogenic program. In addition, activation of TF via PGC-1α will help mediate several beneficial effects of ApN. First, expression of different target genes will increase mitochondrial biogenesis and function and favors an oxidative and more resistant myofiber phenotype. Second, increased expression and production of utrophin, which is a dystrophin analogue, and of antioxidant enzymes, which reduce oxidative stress, will greatly protect the dystrophic muscle against excessive damage. Third, up-regulation of miR-711 will significantly hinder inflammasome priming and activation, and further repress NF-κB activity, thus helping to put a brake on muscle inflammation. Thus far, these properties have been tested on skeletal muscle from mdx mice and confirmed in human DMD myotubes. Pointed head black arrows indicate activation or induction, while blunt head red arrows indicate inhibition. Dashed and blurred circles represent removal of the indicated residue. Boxes with processes in green represent net beneficial effects of ApN, while boxes with processes in red represent deleterious factors inhibited by ApN. ApN, adiponectin. TF, transcription factors. Created with BioRender.com.