MOTS-c-modified functional self-assembly peptide hydrogels enhance the activity of nucleus pulposus-derived mesenchymal stem cells of intervertebral disc degeneration.

Lin Y, Yang RY, Li J, Shao SZ, Shi XQ, Huang ZW, Zhang SH, Liu FJ, Zhang YS, Zhang SQ, Zhang SM, Wen TY, Tao H

Materials today. Bio22 May 2025Cited by 6 (Europe PMC)

PMID40510834PMCIDPMC12159495DOI10.1016/j.mtbio.2025.101872PepBankPUB-40510834

Summary

Intervertebral disc degeneration (IDD) is characterized by oxidative-stress driven progressive apoptosis and senescence of nucleus pulposus mesenchymal stem cells (NP-MSCs). MOTS-c, a 16-amino acid peptide encoded by the mitochondrial 12S rRNA open reading frame, has emerged as a key regulator of cellular metabolism, oxidative stress, and senescence. This study investigated the therapeutic potential of MOTS-c in countering tert-butyl hydroperoxide (TBHP)-induced oxidative damage in NP-MSCs, and we developed a novel biomaterial strategy for IDD treatment.Key findings include.Mechanistic protectionMOTS-c significantly attenuated TBHP-induced NP-MSC apoptosis (Annexin V+/PI + cells reduced by 48 %, p < 0.001), senescence (SA-β-gal + cells decreased by 52 %, p < 0.005), and ROS overproduction (35 % reduction, p < 0.0001) via activation of the AMPK/SIRT1 pathway. Pharmacological inhibition of SIRT1 abolished these protective effects, confirming pathway specificity.Functional hydrogel designA sustained-release MOTS-c delivery system (RAD/RMOTS-c) was engineered by conjugating MOTS-c to the self-assembling RADA16-I peptide. The hydrogel exhibited a β-sheet-rich nanofibrous structure (fiber diameter: 362.6 nm), shear-thinning rheology (viscosity: 131-217 Pa s), and sustained peptide release over 7 days.In vitro efficacyRAD/RMOTS-c enhanced NP-MSC viability (1.8-fold vs. control, p < 0.005) and extracellular matrix (ECM) synthesis, elevating collagen II/aggrecan expression (2.3-fold, p < 0.05) while suppressing collagen I (63 % reduction, p < 0.001).In Vivo Therapeutic Validation: In a rat IDD model, RAD/RMOTS-c injection preserved disc height (DHI%: 82.4 vs. 58.7 in IDD group, p < 0.001), restored T2-weighted MRI signals (1.5-fold increase, p < 0.001), and reduced histological degeneration scores by 44 % compared to untreated controls (p < 0.001).Innovation and impactThis work (1) demonstrates the association between MOTS-c's anti-degenerative effects and AMPK/SIRT1 signaling in NP-MSCs and (2) pioneers a peptide-hydrogel hybrid system that synergistically combines mitochondrial protection with structural support for disc regeneration. The findings can advance IDD therapy toward biology-driven, minimally invasive solutions, aligning with the paradigm of functional biomaterials for degenerative diseases.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study13

5 results from studies that gave the peptide. No result from this study comes from people.

01LabIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells with TBHP-induced oxidative damage, MOTS‑c reduced apoptosis by 48%.
In plain wordsIn lab cells from spinal discs, MOTS‑c reduced oxidative-damage-induced cell death by 48%.
Peptide
MOTS-c
Outcome
DecreaseTBHP-induced NP-MSC apoptosis
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells with TBHP damage
Outcome group
Neuroprotection · Musculoskeletal
Studied dose
Dose not stated
Measurements
Apoptotic cells reduction
48%
Annexin V+/PI+ cells
Source sentences
Summary
MOTS-c significantly attenuated TBHP-induced NP-MSC apoptosis (Annexin V+/PI + cells reduced by 48 %, p < 0.001)
Show in the study text Report a problemFND-4051083401
02LabIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells with TBHP-induced oxidative damage, MOTS‑c decreased senescent (SA-β-gal positive) cells by 52%.
In plain wordsIn lab cells from spinal discs, MOTS‑c reduced oxidative-damage-induced cell aging by 52%.
Peptide
MOTS-c
Outcome
DecreaseTBHP-induced NP-MSC senescence
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells with TBHP damage
Outcome group
Aging markers · Musculoskeletal
Studied dose
Dose not stated
Measurements
SA-β-gal+ cells decrease
52%
TBHP-treated NP-MSCs
Source sentences
Summary
senescence (SA-β-gal + cells decreased by 52 %, p < 0.005)
Show in the study text Report a problemFND-4051083402
03LabIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells with TBHP-induced oxidative damage, MOTS‑c reduced ROS overproduction by 35%.
In plain wordsIn lab cells from spinal discs, MOTS‑c reduced oxidative-damage-induced reactive oxygen by 35%.
Peptide
MOTS-c
Outcome
DecreaseTBHP-induced ROS overproduction
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells with TBHP damage
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Measurements
ROS reduction
35%
TBHP-treated NP-MSCs
Source sentences
Summary
ROS overproduction (35 % reduction, p < 0.0001)
Show in the study text Report a problemFND-4051083403
04LabIn vitro (cells)Mechanism
In nucleus pulposus mesenchymal stem cells, MOTS‑c protection against TBHP damage occurred via activation of the AMPK/SIRT1 pathway.
In plain wordsIn lab cells from spinal discs, MOTS‑c protected against damage through the AMPK/SIRT1 pathway.
Peptide
MOTS-c
Outcome
Not applicableAMPK/SIRT1 pathway involvement in MOTS-c protection
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells with TBHP damage
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
via activation of the AMPK/SIRT1 pathway.
Show in the study text Report a problemFND-4051083404
05LabIn vitro (cells)Mechanism
In nucleus pulposus mesenchymal stem cells, pharmacological inhibition of SIRT1 abolished the protective effects of MOTS‑c.
In plain wordsIn lab cells from spinal discs, blocking SIRT1 removed the protective effects of MOTS‑c.
Peptide
MOTS-c
Outcome
Not applicableEffect of SIRT1 inhibition on MOTS-c protection
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells with TBHP damage
Comparator
SIRT1 inhibition
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
Pharmacological inhibition of SIRT1 abolished these protective effects, confirming pathway specificity.
Show in the study text Report a problemFND-4051083405

Studies that did not test the peptide alone8

In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking MOTS-c.

06AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In a rat model of intervertebral disc degeneration, RAD/RMOTS-c injection preserved disc height (DHI% 82.4 versus 58.7 in the IDD group).
In plain wordsIn rats with disc degeneration, injection of the MOTS‑c hydrogel kept disc height higher than in untreated rats.
Peptide
MOTS-c
Outcome
IncreaseDisc height index in rat IDD model
Study
ratn: not reported in source
intervertebral disc degeneration
Comparator
IDD group
Outcome group
Bone and joint · Musculoskeletal
Measurements
DHI%
82.4%
RAD/RMOTS-c
DHI%
58.7%
IDD group
Source sentences
Summary
RAD/RMOTS-c injection preserved disc height (DHI%: 82.4 vs. 58.7 in IDD group, p < 0.001)
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083411
07AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In a rat model of intervertebral disc degeneration, RAD/RMOTS-c injection restored T2-weighted MRI signals (1.5-fold increase).
In plain wordsIn rats with disc degeneration, the MOTS‑c hydrogel restored disc MRI signals 1.5-fold.
Peptide
MOTS-c
Outcome
IncreaseT2-weighted MRI signal in rat IDD model
Study
ratn: not reported in source
intervertebral disc degeneration
Outcome group
Bone and joint · Musculoskeletal
Measurements
T2-weighted MRI signal
1.5 fold
RAD/RMOTS-c
Source sentences
Summary
restored T2-weighted MRI signals (1.5-fold increase, p < 0.001)
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083412
08AnimalNot a test of MOTS-c aloneAnimal study (in vivo)Efficacy outcome
In a rat model of intervertebral disc degeneration, RAD/RMOTS-c injection reduced histological degeneration scores by 44% compared with untreated controls.
In plain wordsIn rats with disc degeneration, the MOTS‑c hydrogel lowered tissue damage scores by 44% compared with untreated rats.
Peptide
MOTS-c
Outcome
DecreaseHistological degeneration score in rat IDD model
Study
ratn: not reported in source
intervertebral disc degeneration
Comparator
Untreated controls
Outcome group
Bone and joint · Musculoskeletal
Measurements
Histological degeneration score reduction
44%
RAD/RMOTS-c vs untreated
Source sentences
Summary
reduced histological degeneration scores by 44 % compared to untreated controls (p < 0.001).
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083413
09LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells, the RAD/RMOTS-c hydrogel increased viability 1.8-fold versus control.
In plain wordsIn lab cells from spinal discs, the MOTS‑c hydrogel raised cell survival 1.8-fold compared with control.
Peptide
MOTS-c
Outcome
IncreaseNP-MSC viability with RAD/RMOTS-c
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells
Comparator
Control
Outcome group
Neuroprotection · Musculoskeletal
Measurements
Viability fold change
1.8 fold
RAD/RMOTS-c vs control
Source sentences
Summary
RAD/RMOTS-c enhanced NP-MSC viability (1.8-fold vs. control, p < 0.005)
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083408
10LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells, the RAD/RMOTS-c hydrogel increased collagen II and aggrecan expression 2.3-fold.
In plain wordsIn lab cells from spinal discs, the MOTS‑c hydrogel raised disc-matrix genes 2.3-fold.
Peptide
MOTS-c
Outcome
IncreaseCollagen II and aggrecan expression with RAD/RMOTS-c
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells
Outcome group
Bone and joint · Musculoskeletal
Measurements
Collagen II/aggrecan expression
2.3 fold
RAD/RMOTS-c
Source sentences
Summary
elevating collagen II/aggrecan expression (2.3-fold, p < 0.05)
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083409
11LabNot a test of MOTS-c aloneIn vitro (cells)Efficacy outcome
In nucleus pulposus mesenchymal stem cells, the RAD/RMOTS-c hydrogel reduced collagen I expression by 63%.
In plain wordsIn lab cells from spinal discs, the MOTS‑c hydrogel lowered collagen I by 63%.
Peptide
MOTS-c
Outcome
DecreaseCollagen I expression with RAD/RMOTS-c
Study
n: not reported in source
nucleus pulposus mesenchymal stem cells
Outcome group
Bone and joint · Musculoskeletal
Measurements
Collagen I reduction
63%
RAD/RMOTS-c
Source sentences
Summary
suppressing collagen I (63 % reduction, p < 0.001)
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083410
12LabNot a test of MOTS-c aloneIn vitro (cell-free)Other
The RAD/RMOTS-c hydrogel (MOTS‑c conjugated to RADA16-I) had a beta-sheet-rich nanofibrous structure with a fiber diameter of 362.6 nm and shear-thinning viscosity of 131-217 Pa s.
In plain wordsIn lab tests, the MOTS‑c peptide hydrogel formed nanofibers and thinned under shear.
Peptide
MOTS-c
Outcome
Not applicableHydrogel nanofiber structure and rheology
Study
n: not reported in source
RAD/RMOTS-c hydrogel
Outcome group
Receptor activity and mechanism · Musculoskeletal
Measurements
Fiber diameter
362.6 nm
RAD/RMOTS-c hydrogel
Viscosity
131 to 217 Pa s
RAD/RMOTS-c hydrogel
Source sentences
Summary
The hydrogel exhibited a β-sheet-rich nanofibrous structure (fiber diameter: 362.6 nm), shear-thinning rheology (viscosity: 131-217 Pa s)
1 context sentence(design, population, supporting numbers)
Summary · context
A sustained-release MOTS-c delivery system (RAD/RMOTS-c) was engineered by conjugating MOTS-c to the self-assembling RADA16-I peptide.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083406
13LabNot a test of MOTS-c aloneIn vitro (cell-free)Pharmacokinetics
The RAD/RMOTS-c hydrogel showed sustained peptide release over 7 days.
In plain wordsIn lab tests, the MOTS‑c peptide hydrogel released peptide steadily over 7 days.
Peptide
MOTS-c
Outcome
Not applicableSustained peptide release from the hydrogel
Study
n: not reported in source
RAD/RMOTS-c hydrogel
Outcome group
Pharmacokinetics · Musculoskeletal
Measurements
Release duration
7 days
RAD/RMOTS-c hydrogel
Source sentences
Summary
and sustained peptide release over 7 days.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-4051083407

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Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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