Audrey Kelley

Introduction: Type 2 Diabetes Mellitus (T2DM) is the most common metabolic disease in the world, and is characterized by an insufficient response to insulin with subsequent glucose accumulation in the blood.^1,2 High-fat diets contribute to the development and progression of the disease by downregulating the expression of glucose uptake transporter 4 (GLUT4) in skeletal muscle, which reduces the transport of glucose from the blood to the skeletal muscle.^1,3,4 Interventions for T2DM include lifestyle modifications, such as increasing physical activity.^1,2 Aerobic activity is important in preventing and managing T2DM because it establishes a state of metabolic stress on the skeletal muscle cells which enhances the expression of the mitochondrial protein, MOTS-c.^5,6 MOTS-c is derived from the mitochondrial open reading frame of the 12S rRNA-c and promotes homeostasis by upregulating GLUT4 in the skeletal muscle.⁶ Methods: To explore the effects of acute exercise on endogenous expressions of MOTS-c, human participants performed an acute high-intensity cycling exercise session. Skeletal muscle and plasma samples were obtained pre-, immediately post-, and 4-hours post-workout. One additional plasma sample was obtained mid-workout. The MOTS-c levels in the samples were analyzed via ELISA and Western Blotting.⁵ In a separate study, the ability of MOTS-c to upregulate GLUT4 expression in obese mice was determined by placing mice on a high-fat diet (HFD) consisting of a 40% lipid energy source. Mice received daily intraperitoneal injections of recombinant MOTS-c and/or participated in treadmill exercise for 8-weeks. Afterwards, skeletal muscle samples were obtained, GLUT4 levels were determined using immunoblotting, and glucose tolerance tests were performed assessing insulin sensitivity.⁶ Results: Acute exercise increased MOTS-c levels in skeletal muscle and plasma samples. Plasma MOTS-c levels peaked mid-workout and declined to pre-workout levels 4-hours post-workout. Skeletal muscle MOTS-c levels were significantly increased immediately post-workout and remained increased at 4-hours post-workout with a downward trend.⁵ Treadmill training and intraperitoneal injections of MOTS-c in HFD, obesity-induced mice increased skeletal muscle GLUT4 expression and improved insulin sensitivity compared to the control HDF, obesity-induced mice. GLUT4 and insulin sensitivity were further enhanced when combining exercise training and MOTS-c injections.⁶ Conclusion: Endogenous expression of MOTS-c increases following acute bouts of high-intensity aerobic exercise and intraperitoneal injections of MOTS-c.^5,6 MOTS-c upregulates the expression of skeletal muscle GLUT4 which removes glucose from the blood and improves the individual’s insulin sensitivity.^1,6 Combining aerobic exercise with MOTS-c administration may be more effective than either treatment alone in attenuating the development and progression of T2DM.

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3. Kim SJ, Miller B, Mehta H, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep. 2019;7(13):e14171. doi:10.14814/phy2.14171
4. Boon J, Hoy AJ, Stark R, et al. Ceramides Contained in LDL Are Elevated in Type 2 Diabetes and Promote Inflammation and Skeletal Muscle Insulin Resistance. Diabetes. 2013;62(2): 401–410. doi: 10.2337/db12-0686
5. Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. doi:10.1038/s41467-020-20790-0
6. Yang B, Yu Q, Chang B, et al. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1α expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochim Biophys Acta Mol Basis Dis. 2021;1867(6):166126. doi: 10.1016/j.bbadis.2021.166126