Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling

Takada, Shingo; Masaki, Yoshihiro; Kinugawa, Shintaro; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Kadoguchi, Tomoyasu; Fukushima, Arata; Homma, Tsuneaki; Takahashi, Masashige; Harashima, Shin‐ichi; Matsushima, Shouji; Yokota, Takashi; Tanaka, Shinya; Okita, Koichi; Tsutsui, Hiroyuki

doi:10.1093/cvr/cvw182

Cited by 67 publications

(63 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a consequence, muscle mass and muscle function improved in Dex‐induced muscle atrophy mice. In support of our results, recent studies reported that the inhibitors of DPP4, a GLP‐1 degradation enzyme, are associated with improvement of reduced muscle mass in diabetic and elderly diabetic patients and with improvement of mitochondrial biogenesis in a heart failure mouse model …”

Section: Discussionsupporting

confidence: 90%

“…Therefore, GLP‐1‐based drugs have been developed as an anti‐diabetic therapy. Although some studies have implicated the possible effects of GLP‐1‐based drugs on muscle mass, metabolism, and function, little is known about the precise mechanisms underlying its effects . Therefore, we investigated whether GLP‐1‐based drugs have a therapeutic effect in muscle wasting.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“…Sitagliptin has been shown to increase GLUT‐4 expression in skeletal muscle of type 2 diabetic rats and hypertensive rats . MK‐0626, a DPP‐4 inhibitor, was associated with improvements in mitochondrial biogenesis in skeletal muscle and improvement in exercise capacity of mice who had suffered recent myocardial infarction . In another study, the effects of linagliptin on an animal model of premature aging supported a positive role in preventing muscle loss, based on the larger size of the gastrocnemius muscle in linagliptin‐treated mice compared with control .…”

Section: Drugs and Musclementioning

confidence: 94%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

View full text Add to dashboard Cite

Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

show abstract

“…The myokine dipeptidyl-peptidase 4 (DPP4) has recently come in the spotlight because its inhibition, as well as the use of glucagon-like receptor 1 (GLP-1) agonists, leads to an antistroke effect [137, 138] and a cardioprotective role [139]. During physical exercise, DPP4 inhibitors improve mitochondrial biogenesis and muscle activity through the activation of GLP-1 signaling [140]. Yet, this myokine should act at a more systemic level, in the energetic balance of the organism, as their inhibitors are able to act in a similar way to sulfonylureas or pioglitazone for diabetes [141].…”

Section: Bone-skeletal Muscle Biomarkers In Strokementioning

confidence: 99%

Assessed and Emerging Biomarkers in Stroke and Training-Mediated Stroke Recovery: State of the Art

et al. 2017

View full text Add to dashboard Cite

Since the increasing update of the biomolecular scientific literature, biomarkers in stroke have reached an outstanding and remarkable revision in the very recent years. Besides the diagnostic and prognostic role of some inflammatory markers, many further molecules and biological factors have been added to the list, including tissue derived cytokines, growth factor-like molecules, hormones, and microRNAs. The literatures on brain derived growth factor and other neuroimmune mediators, bone-skeletal muscle biomarkers, cellular and immunity biomarkers, and the role of microRNAs in stroke recovery were reviewed. To date, biomarkers represent a possible challenge in the diagnostic and prognostic evaluation of stroke onset, pathogenesis, and recovery. Many molecules are still under investigation and may become promising and encouraging biomarkers. Experimental and clinical research should increase this list and promote new discoveries in this field, to improve stroke diagnosis and treatment.

show abstract

Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling

Abstract: A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle.

Cited by 67 publications

References 39 publications

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Diabetes pharmacotherapy and effects on the musculoskeletal system

Assessed and Emerging Biomarkers in Stroke and Training-Mediated Stroke Recovery: State of the Art

Contact Info

Product

Resources

About