MOTS-c: an equal opportunity insulin sensitizer

MOTS-c is a 16-amino acid peptide encoded from 12S rRNA region of the mitochondrial DNA [1]. Multiple publications support the notion that MOTS-c plays an important role in regulating metabolism and insulin action and it has been suggested that MOTS-c exerts exercise mimetic effects in rodents [2]. In this issue of the Journal of Molecular Medicine, Lu et al. [3] revealed an important new role of MOTS-c as a hormone capable of preventing negative metabolic effects associated with menopause in an ovariectomized mouse model. These investigators found that MOTS-c treatment reduced both the weight gain as well as the insulin resistance associated with experimental menopause. Furthermore, they found that MOTS-c also suppressed the increase in inflammatory markers such as IL-1ß and IL-6 in adipose tissue. This anti-inflammatory effect may be key in the health-promoting effects of MOTS-c.

It is well known that postmenopausal women exhibit physiological alterations including weight gain, changes in adipose tissue distribution, and deterioration of insulin secretion, and sensitivity [4, 5]. These changes predispose them to develop type 2 diabetes [4]. Furthermore, decreased levels of estrogen are associated with non-alcoholic steatohepatitis, osteoporosis, and cardiovascular diseases [6-8]. These menopausal-associated metabolic abnormalities and health problems can be alleviated by exercise, whose benefits are obtained via diverse mechanisms including decreased inflammatory mediators, increased activity of antioxidants, and improved endothelial function [9, 10]. A recent meta-analysis on the effects of programmed exercise on insulin sensitivity-related outcomes in postmenopausal women revealed that exercising for three to four months significantly lowers insulin levels, and improves HOMA-IR, BMI, waist circumference, and body fat mass [11]. Exercise, which induces muscle remodeling, is beneficial not only for menopause but also for multiple other chronic diseases. Previous studies have shown that regular aerobic exercise such as walking, running, or high physical fitness has protective effects against obesity, type 2 diabetes, and cardiovascular disease [12-14]. Given the sedentary lifestyle in western societies, developing exercise mimetics offers a promising therapeutic strategy for chronic diseases [15].

The development of such exercise mimetic drugs requires a better understanding of the molecular mechanisms involved in exercise-induced muscle remodeling. Muscle is not only a locomotive organ but also an endocrine organ. Muscle releases multiple myokines during exercise, and these myokines likely mediate many of the systemic effects of exercise [16].

Mitochondria not only provide muscle with the necessary fuel, but also release and integrate exercise-induced signaling. AMPK, SIRT1, and PGC1α are central to exercise-induced signaling and are activated in skeletal muscles during exercise, leading to fatty acid oxidation and mitochondrial biogenesis [17]. These processes are followed by muscle remodeling that leads to exercise endurance and metabolic improvements. Indeed, small molecules and naturally occurring compounds that activate AMPK and SIRT1 exert exercise mimetic effects including insulin sensitization protect against diet-induced metabolic dysfunction in mice [18].

MOTS-c has been proposed to be a mitochondrial-derived exercise-mimetic myokine [1]. MOTS-c is expressed in skeletal muscles and other tissues and is detected in plasma. MOTS-c increases endogenous AICAR levels and activates AMPK [1]. In addition, MOTS-c increases NAD+ levels, and SIRT1 is partially involved in MOTS-c actions [1]. MOTS-c also increases insulin sensitivity in skeletal muscle from aged, and high-fat fed, mice [1]. Furthermore, MOTS-c dramatically decreases weight gain during high-fat-diet-induced obesity in mice, and prevents fat accumulation in liver, making it a potential target in NASH (Figure-1) [1, 19]. The paper by Lu and colleagues, suggests that brown adipose tissue (BAT) may also be a direct target of MOTS-c, affecting mitochondrial number and function in this tissue [3]. Lu et al. also show that MOTS-c administration also prevents ovariectomy-induced obesity and insulin resistance in mice via the AMPK pathway. Previous studies revealed that MOTS-c prevents ovariectomy-induced osteoporosis in mice and that it promotes differentiation of bone mesenchymal stem cell to osteoblasts in a rat model [20, 21].

Figure 1.

MOTS-c ameliorates various multiple resistant states.

Taken together, MOTS-c is a mitochondrial derived exercise mimetic affecting a variety of chronic diseases of aging, but remarkably, as Lu et al. as well as Lee et al. showed, has no effect on rodents that aren’t metabolically challenged (Table-1). In addition, MOTS-c assays could emerge as biomarkers of metabolic dysfunction. Plasma MOTS-c levels are lower in obese male children and adolescents, and are negatively correlated with markers of insulin resistance [22, 23]. MOTS-c levels are also positively correlated with coronary endothelial function in humans, and MOTS-c improves endothelial function in rats [24]. However, the metabolic beneficial effects were observed only in male mice but not in pre-menopausal female mice [22]. Further studies understanding this sexual dimorphism of MOTS-c will extend our understanding of its biology.

Table 1.

MOTS-c alleviates various pathological conditions

Pathological conditions	MOTS-c action	References
Aging-associated insulin resistance	Increases glucose uptake in skeletal muscles in aged mice.	[1]
High-fat diet (HFD)-insulin resistance	Increases insulin sensitivity in HFD-fed mice. Increases GLUT-4 expression in skeletal muscle in HFD-fed mice.	[1]
Obesity-associated insulin resistance	Plasma MOTS-c levels are lower in obese male children and adolescents and negatively correlated with markers of insulin resistance and obesity.	[22, 23]
Nonalcoholic steatohepatitis	Decreases hepatic fat accumulation in HFD-fed mice. MOTS-c analogues prevent NASH in a STAM model	[1,19]
Endothelial dysfunction	Improves endothelial function in rats. Plasma MOTS-c levels are lower in human subjects with impaired coronary endothelial function.	[24]
Menopause-associated conditions	Prevents ovariectomy-induced obesity and insulin resistance. Alleviates ovariectomy-induced osteoporosis.	[3, 20]
Osteoporosis/Osteopenia	Alleviates bone loss in ovariectomy-induced osteoporosis via AMPK. Promotes rat bone mesenchymal stem cells differentiation to osteoblasts via TGF-β pathway.	[20, 21]
Sepsis	Improves survival in mice during MRSA infection. Enhances bactericidal capacity of macrophages in MRSA-infected mice.	[34]

MOTS-c directly connects the mitochondria to exercise-induced signaling. Mitochondria are semiautonomous organelles with the capacity to transcribe and translate 13 large proteins and multiple mitochondrial-derived peptides (MDPs) including MOTS-c [25]. MDPs are a group of peptides with potent biological activities and effects on mitochondrial functions and systemic metabolism [25, 26]. MDPs modulate mitochondrial respiration, mitochondrial biogenesis, and mitochondrial ROS production [27-30]. Humanin, the first MDP discovered, has been extensively characterized as a cytoprotective molecule that can attenuate Alzheimer’s disease-related pathology, endothelial dysfunction, and macular degeneration [30-32]. The discovery of humanin represented a paradigm shift in the field of genetics, which has led to discoveries of multiple bioactive peptides encoded by small open reading frames in nuclear and mitochondrial DNA including the family of small humanin like peptides 1-6 (SHLPs), MOTS-c and more such peptides are likely to be discovered and characterized [33, 35].