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Muscle wasting in diabetes: stop it by tagging the protein @ www.klf15.ub

Diabetes mellitus is a disease caused by insufficient action of the hormone insulin. Insulin not only lowers blood sugar levels, but promotes the growth and proliferation of cells; insufficient action of insulin has been thought to result in the suppression of growth and proliferation of muscle cells, which in turn contribute to the decline in skeletal muscle mass. Diabetes mellitus is associated with various health problems including decline in skeletal muscle mass. Muscle mass decline associated with aging impairs our physical activity, making us susceptible to a variety of health problems and thus leading to shortened lifespans. Age-dependent muscle mass decline and the consequent impairment of physical activity is known as “sarcopenia” (muscle wasting), a serious health burden in aging societies. Scientists already knew that patients with diabetes mellitus are prone to muscle loss as they age, but an underlining mechanism for this phenomenon remains unclear. A research group led by Professor Wataru Ogawa at the Kobe University Graduate School of Medicine revealed that elevation of blood sugar levels leads to muscle atrophy and that two proteins, WWP1 and KLF15, play a key role.

Professor Ogawa’s research team made the surprising discovery that a rise in blood sugar levels triggers the decline in muscle mass, and uncovered the important roles of two proteins in this phenomenon. They found that the abundance of transcription factor KLF15 increased in skeletal muscle of diabetic mice, and mice that lack KLF15 specifically in muscle were resistant to diabetes-induced skeletal muscle mass decline. These results indicate that diabetes-induced muscle loss is attributable to increased amounts of KLF15. The team investigated the mechanism for how the abundance of KLF15 is increased in skeletal muscle of diabetic mice. They found that elevation of blood sugar levels slows down the degradation of KLF15 protein, which leads to an increased amount of this protein. Professor Ogawa’s team also discovered that a protein called WWP1 plays a key role in regulating the degradation of KLF15 protein. WWP1 is a member of enzymes called ubiquitin ligases.  When a small protein called “ubiquitin” binds to other proteins, the degradation of the ubiquitin-bound proteins is accelerated. It works like a “chemical tag” for distruction.

Under normal conditions, WWP1 promotes the degradation of KLF15 protein by binding ubiquitins to KLF15, keeping cellular KLF15 abundance low. When blood sugar levels rise, the amount of WWP1 decreases, which in turn decelerates the degradation of KLF15 and thus the increase in the cellular abundance of KLF15. This study uncovered for the first time that elevation of blood sugar levels triggers muscle mass decline, and that the two proteins WWP1 and KLF15 contribute to diabetes-induced muscle mass decline. There is a curious connection between these two proteins and the metabolism of the muscles. In particular, the KLF15 factor is regulated by the branched-chain amino acids (BCAAs), which are important stabilizers of muscle mass. The keep KLF15 low by activating growth-promoting cellular signaling, like the PI3K-Akt axis. Moreover, leucine, isoleucine and valine are important modulators of metabolism. For example, their catabolism yields carbon substrates for gluconeogenesis during periods of fasting.

KLF15 has recently emerged as a critical transcriptional regulator of BCAA metabolism, and the absence of this transcription factor contributes to severe pathologies, such as Duchenne muscular dystrophy and heart failure. As well as diabetes mellitus, other conditions such as physical inactivity or ageing result in muscle mass loss. The proteins KLF15 and WWP,1 which have been shown to contribute to diabetes-induced muscle mass loss, may also be related to other causes of muscle loss. Professor Ogawa concluded: “Currently, no drug is available for the treatment of muscle loss. If we develop a drug that strengthens the function of WWP1 or weakens the function of KLF15, it would lead to a groundbreaking new treatment”. These findings were published on February 21 in the online edition of JCI Insight.

  • Edited by Dr. GIanfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Cho EB et al. Biochim Biophys Acta Mol Basis Dis. 2018;1864:2199. 

Imamura M et al., Takeda S. J Biochem. 2016 Feb; 159(2):171-79.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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