Myogenetic oligodeoxynucleotide (myoDN) recovers the differentiation of skeletal muscle myoblasts deteriorated by diabetes mellitus

Abstract

Sarcopenic obesity is a complication of decreased muscle mass and strength associated with obesity, and sarcopenia associated with diabetes mellitus (DM) is a serious risk factor that may result in mortality. Deteriorated differentiation of muscle precursor cells, called myoblasts, in DM patients is considered to be one of the causes of muscle atrophy. We recently developed myogenetic oligodeoxynucleotides (myoDNs), which are 18-base single-strand DNAs that promote myoblast differentiation by targeting nucleolin. Herein, we report the applicability of a myoDN, iSN04, to myoblasts isolated from patients with type 1 and type 2 DM. Myogenesis of DM myoblasts was exacerbated concordantly with a delayed shift of myogenic transcription and induction of interleukins. Analogous phenotypes were reproduced in healthy myoblasts cultured with excessive glucose or palmitic acid, mimicking hyperglycemia or hyperlipidemia. iSN04 treatment recovered the deteriorated differentiation of plural DM myoblasts by downregulating myostatin and interleukin-8. iSN04 also ameliorated the impaired myogenic differentiation induced by glucose or palmitic acid. These results demonstrate that myoDNs can directly facilitate myoblast differentiation in DM patients, making them novel candidates for nucleic acid drugs to treat sarcopenic obesity.

Myogenetic oligodeoxynucleotide restores differentiation and reverses inflammation of myoblasts aggravated by cancer-conditioned medium

“…The protective effect of iSN04 against cancer secretions is expected to prevent deteriorated differentiation and inflammation in myoblasts of cancer patients. Myogenetic and anti-inflammatory effects of iSN04 have also been reported in diabetic human myoblasts [15]. These studies support that iSN04 can be a potential nucleic acid drug to prevent disease-associated muscle wasting along with systemic chronic inflammation such as cancer cachexia.…”

“…The results are presented as fold-changes. Primer sequences (5’-3’) were as follows: myomaker ( MYMK ), CCC TGA TGC TAC GCT TCT TC and TCC AGC CTT CTT GTT GAC CT; myomixer ( MYMX ), ATC CAG CCA GAG ACT GAT TC and AGG ACA GCA GCA ATC GAA G. Primer sequences of IL-1β ( IL1B ), IL-6 ( IL6 ), IL-8 ( CXCL8 ), MyoD ( MYOD1 ), myogenin ( MYOG ), myostatin ( MSTN ), nuclear factor-κB (NF-κB) p50 subunit ( NFKB1 ), and TNF-α ( TNF ) were described previously [14,15].…”

“…We recently reported that single-strand short DNAs named myogenetic oligodeoxynucleotides (myoDNs) promote the differentiation of myoblasts and rhabdomyosarcoma [14–17]. One of the myoDNs, iSN04, serves as an anti-nucleolin aptamer to increase p53 translation [14] and recovers myoblast differentiation attenuated by diabetes mellitus [15], demonstrating that iSN04 is a potential nucleic acid drug for disease-associated muscle wasting. The present study investigated whether iSN04 affects myogenesis and inflammation in human myoblasts cultured in colon cancer-CM mimicking cancer cachexia.…”

Myogenetic Oligodeoxynucleotide (myoDN) Recovers the Differentiation of Skeletal Muscle Myoblasts Deteriorated by Diabetes Mellitus

“…The preprint has been posted on bioRxiv ( Nakamura et al, 2021 ).…”

Identification of a Novel Osteogenetic Oligodeoxynucleotide (osteoDN) that Promotes Osteoblast Differentiation in a TLR9-Independent Manner

“…We recently screened an 18-base ODN library designed from the genome sequence of the lactic acid bacterium Lacticaseibacillus rhamnosus GG [17] to determine its effect on myogenic differentiation. The 18-base guanine (G)-rich ODN, iSN04, promoted differentiation and suppressed inflammation in myogenic precursor cells called myoblasts [18][19][20][21][22]. iSN04, termed myogenetic ODN (myoDN), formed a globular structure of 1-nm radius and served as an anti-nucleolin aptamer in a TLR-independent manner [18].…”