Alzheimer’s Mouse Model Shows Early, Sex-Skewed Skeletal Muscle Decline

Alzheimer’s disease has long been framed as a disorder of the brain, but a new study in the journal GeroScience argues that its reach extends well beyond the central nervous system. In a detailed characterization of the 3xTg-AD mouse model, researchers report that skeletal muscle mass, morphology and function deteriorate early and progressively in these animals, and that the pattern of deterioration differs sharply between males and females. Male mice showed reduced lean mass, muscle weight and torque generation as early as three months of age, while females generally displayed a milder phenotype that emerged later and in some measures never appeared at all.

The 3xTg-AD model carries three human gene mutations linked to familial Alzheimer’s disease: the Swedish mutation of APP, the P301L mutation in MAPT, and the M146V mutation in PSEN1. These mice develop age-dependent amyloid plaques, neurofibrillary tangles, cognitive decline and neuroinflammation, and previous work has reported behavioral alterations in females as early as 2.5 months and cognitive impairment between three and five months. The team, led by Amy Creecy, David L. Waning and Joshua R. Huot with colleagues at Indiana University School of Medicine, compared male and female 3xTg-AD mice with age- and sex-matched B6129 control mice at three, six and twelve months of age, using groups of at least seven and at most fifteen animals per endpoint.

Body composition, measured by dual-energy X-ray absorptiometry, revealed striking sex-specific trajectories. Female 3xTg-AD mice were heavier than controls at six months by 24.1 percent and at twelve months by 28.3 percent, driven by an 11.3 percent increase in lean mass at six months and large gains in fat mass of 92.9 percent at six months and 145.0 percent at twelve months. Male 3xTg-AD mice moved in the opposite direction: whole body weight was 12.8 percent lower at three months and 16.0 percent lower at six months, with no difference at twelve months. The male weight deficit was accompanied by a 16.6 percent reduction in lean mass at three months and reductions in fat mass of 45.1 percent at six months and 63.9 percent at twelve months.

Individual hindlimb muscle weights told a similar story. In females, the quadriceps, gastrocnemius and tibialis anterior weighed less than controls only at the six-month timepoint, while the soleus and extensor digitorum longus were unchanged at every age. In males, the quadriceps, gastrocnemius and tibialis anterior were lighter at both three and six months, the quadriceps remained lighter at twelve months, and the soleus was lighter at six months; the extensor digitorum longus was never affected. The authors note that these sex-by-genotype interactions were statistically significant for all muscle masses, and that muscle mass changes accounted for whole body weight differences to a greater extent in males than in females.

Muscle function testing showed that weakness was not simply a consequence of smaller body size. In vivo plantarflexion torque about the ankle was measured at each age. Female 3xTg-AD mice showed no difference in raw torque, but when torque was normalized to body weight, function was significantly reduced at three months (−12.3 percent), six months (−22.6 percent) and twelve months (−21.7 percent), and when normalized to lean mass it was reduced at six months (−14.1 percent). Male mice fared worse: raw torque was reduced at three months (−16.9 percent), six months (−17.2 percent) and twelve months (−20.0 percent), body-weight-normalized torque was reduced at twelve months (−15.4 percent), and lean-mass-normalized torque was reduced at six months (−13.9 percent) and twelve months (−22.3 percent). When torque was normalized to gastrocnemius weight, no differences appeared in either sex, indicating that the deficits tracked muscle and body size rather than a loss of force per unit of muscle tissue.

The dynamics of contraction and relaxation were also altered. Female mice showed a 13.5 percent reduction in the rate of contraction at six months, with no change in relaxation rate. Males showed reduced contraction rates at three months (−20.1 percent) and six months (−24.4 percent), and slower relaxation at six months (−21.1 percent) and twelve months (−19.2 percent). Notably, fatigue resistance, tested with a short isometric protocol of ten contractions, did not differ at any timepoint in either sex, suggesting that the observed weakness reflects deficits in force production and contractile kinetics rather than premature fatigability.

Histological analysis of the tibialis anterior revealed fiber-type shifts and atrophy. Female mice showed an increase in type IIA fibers at three months and a decrease in type IIB fibers at six months, while males showed increased type IIA fibers at three and twelve months and decreased type IIB fibers at three and six months. Fiber-specific cross-sectional area told a more consistent story of atrophy: in females, type IIA fiber area was reduced at twelve months and type IIB fiber area at six and twelve months; in males, type IIX fiber area was reduced at six months and type IIB fiber area at three, six and twelve months, with a possible compensatory increase in type IIA area that did not reach statistical significance. Total fiber cross-sectional area, a measure of whole-muscle atrophy, was reduced in females at six and twelve months but in males at all three ages examined, mirroring the earlier and more severe functional losses seen in males.

Perhaps the most mechanistically suggestive finding concerned innervation. The team quantified expression of neural cell adhesion molecule, or NCAM, a protein that rises in muscle fibers following denervation or injury and is involved in neuromuscular junction formation. Male 3xTg-AD mice showed significantly increased proportions of NCAM-positive fibers at three, six and twelve months, while females showed an increase only at twelve months. The authors interpret this as evidence that denervation may be at least one cause of the reduced muscle function, pointing toward a neuromuscular junction deficiency, although they caution that NCAM expression could also reflect regenerative responses and that complementary imaging of the neuromuscular junction itself would be needed to distinguish the two.

The study’s design carries some limitations worth noting. Control B6129 mice can exhibit phenotypic variability, an issue the authors acknowledge directly, although they argue that using this background minimizes genetic confounding because the 3xTg-AD line was originally developed on it. The histological and NCAM analyses used five biological replicates per group, smaller than the functional cohorts. The authors also note that because cognitive and muscle outcomes were not assessed concurrently in this study, the temporal relationship between the two cannot be established directly, even though muscle abnormalities were detectable at three months, within the window in which cognitive impairment has been reported in this model.

Taken together, the findings position skeletal muscle as an early, sex-dependent and measurable component of Alzheimer’s disease pathology in this mouse model, with male mice exhibiting earlier and more severe impairments in mass, function and fiber morphology than females. The authors suggest that the milder female phenotype may reflect protective hormonal influences, such as estrogen-driven mitochondrial biogenesis and antioxidant defenses, while the male phenotype may involve earlier mitochondrial dysfunction and proinflammatory signaling. They emphasize that these are hypotheses requiring further study of mitochondrial content, respiratory capacity and neuromuscular junction integrity. If the systemic involvement of skeletal muscle in Alzheimer’s disease is confirmed in humans, the authors argue, muscle could become a modifiable target for preserving mobility, independence and quality of life in affected individuals.

Subject of Research: Sex-dependent skeletal muscle dysfunction in the 3xTg Alzheimer's disease mouse model

Article Title: Characterization of sex-dependent skeletal muscle alterations in the 3xTg Alzheimer’s disease mouse model

Article References: Creecy, A., Waning, D. L., Khurram, I., Warsame, A., Blosser, R. J., Karnik, S. J., Xu, J., Yamada, C., Smith, D. K., Oblak, A. L., Fehrenbacher, J. C., Movila, A., Kacena, M. A., & Huot, J. R. (2026). Characterization of sex-dependent skeletal muscle alterations in the 3xTg Alzheimer’s disease mouse model. GeroScience. https://doi.org/10.1007/s11357-026-02569-1

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02569-1

Keywords: Alzheimer's disease, 3xTg-AD mice, skeletal muscle, sarcopenia, neuromuscular junction, muscle atrophy, NCAM, muscle torque, fiber cross-sectional area, body composition, sex differences, GeroScience