Exercise-Driven MOTS-c Emerges as a Liver-Protective Signal in MASLD
Aerobic exercise restored a mitochondrial peptide signal in skeletal muscle and linked it to a measurable reduction in fatty liver injury in a diabetic MASLD mouse model. The work places MOTS-c at the center of an exercise-to-liver pathway that may help explain why physical activity improves metabolic dysfunction-associated steatotic liver disease even when sustained training is difficult to maintain in daily practice.
In the MASLD mice, circulating MOTS-c, skeletal muscle MOTS-c, and liver MOTS-c were all reduced relative to normal controls. Aerobic exercise reversed that pattern, and skeletal muscle protein expression rose in parallel with tissue staining signals. Exogenous MOTS-c also increased MOTS-c production in skeletal muscle, suggesting an autocrine loop, although exercise produced the stronger rise. The peptide’s instability as a therapeutic injection likely contributes to that gap.
Hepatic Steatosis, Glucose Dysregulation, and the Metabolic Split Between Exercise and Peptide Therapy
The metabolic phenotype in these animals tracked with the peptide changes. Four weeks of MOTS-c administration or aerobic training stabilized body weight while lowering fasting glucose. Glucose tolerance and insulin tolerance both improved, with reduced area under the curve in the intervention groups compared with untreated MASLD mice. Exercise appeared more effective for insulin sensitivity, while MOTS-c showed a stronger effect on glucose intolerance.
One sentence captures the bedside implication: exercise and peptide replacement did not behave as identical interventions.
Liver pathology moved in the same direction. Histology showed less lipid accumulation with either aerobic exercise or MOTS-c treatment, and serum triglycerides fell as hepatic triglyceride content declined. LDL also decreased, while HDL remained unchanged across groups. The liver did not show significant fibrosis in any group, which keeps the focus on early steatotic injury rather than advanced scarring. In this model, the dominant problem was fat overload and inflammatory activation, not fibrotic remodeling.
Lipid Synthesis Fell, Inflammation Fell With It
The mechanistic readout was more specific than a simple improvement in liver appearance. Fatty acid synthesis markers FAS and ACC dropped after MOTS-c or exercise. Inflammatory transcripts IL-1β and TNF-α also fell in both intervention arms, consistent with a less hostile hepatic microenvironment. Aerobic exercise went a step further by increasing fatty acid oxidation genes ACOX1 and CPT-1, a pattern not seen with MOTS-c alone.
That split matters biologically. Reduced lipogenesis lowers the incoming lipid burden, while higher β-oxidation improves disposal of fatty acids already present in the liver. Exercise can drive both sides of that ledger through systemic energy expenditure, muscle-liver crosstalk, and mitochondrial adaptation. MOTS-c seems to reproduce part of the program, but not the full metabolic remodeling triggered by physical training.
ACE2 Recovery Points to a Hepatic Renin-Angiotensin Pathway
The most important mechanistic finding centered on hepatic ACE2. MASLD mice showed reduced liver ACE2 expression, while both MOTS-c and aerobic exercise restored it. In HepG2 cells exposed to palmitic acid, ACE2 protein again fell under metabolic stress and partially recovered after MOTS-c treatment. The AMPK inhibitor Compound C blocked the MOTS-c-induced rise in ACE2, placing AMPK upstream of this response.
This sequence fits the broader biology of the liver renin-angiotensin system. When ACE2 activity is reduced, the balance shifts away from the protective ACE2/Ang1-7/Mas axis and toward a more injurious state associated with lipid accumulation and metabolic stress. Restoring ACE2 offers a plausible route to reducing steatosis and inflammation without needing to directly suppress fat intake or insulin resistance at the receptor level. The data also align with the observed reduction in pAMPK in MASLD mice, which was partially reversed by MOTS-c intervention.
What the Mouse Data Can and Cannot Claim
The study supports a model in which aerobic exercise stimulates skeletal muscle to secrete MOTS-c, and MOTS-c then acts on the liver to raise ACE2 through AMPK signaling. That chain of events offers a coherent explanation for part of exercise’s benefit in MASLD, especially in people who struggle to sustain physical training because of sedentary habits or mobility limitation. The authors also frame MOTS-c as a possible option for patients with sarcopenia related to cirrhosis, where exercise tolerance is often poor.
The findings remain preclinical, and every translational step still needs proof. The work was done in mice and HepG2 cells, not in people with MASLD. The model also combined high-fat feeding with streptozotocin-induced diabetes, which may not mirror every clinical MASLD phenotype. Exogenous MOTS-c was delivered by intraperitoneal injection, and the study itself points out that peptide instability may limit its apparent potency compared with exercise.
Even with those limits, the biological message is precise. Skeletal muscle is not acting only as an engine for exercise; it is functioning as an endocrine organ that sends a mitochondrial peptide signal to the liver. In this model, that signal was enough to reduce steatosis, calm inflammatory signaling, and restore a protective hepatic receptor pathway tied to ACE2 and AMPK. The remaining question is not whether the pathway is interesting. It is how much of it can be reproduced safely, durably, and with clinically practical dosing in human MASLD.