Targeting collagen cross-linking to support aged muscle hypertrophy

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With advancing age, the capacity for skeletal muscle to adapt to mechanical load is attenuated, limiting the ability of older adults to maintain muscle mass and strength. An essential component of this process is the turnover and reorganization of the extracellular matrix (ECM), which provides a scaffold for muscle fiber growth and supports its structural integrity. As organisms age, the skeletal muscle ECM becomes more cross-linked, which makes the matrix difficult to remodel and is thought to contribute to age-related declines in hypertrophy and strength. Thus, the objective of our study was to assess if the ECM contributed to anabolic resistance in aged muscle hypertrophy. We hypothesized that older mice would exhibit blunted hypertrophy and increased collagen content and cross-linking following mechanical overload compared to younger mice. Adult (4-6 months) and aged (24-28 months) mice underwent mechanical overload of the plantaris by surgical ablation of the gastrocnemius-soleus complex. Aged mice show a dampened increase in bodyweight normalized muscle mass (Adult: 1.089 mg/g, Aged: 0.6991 mg/g, p=0.003) and fiber cross-sectional area (Adult: 1829 µm2, Aged: 1461 µm2, p=0.0398), but an accentuated increase in collagen content (Adult: 0.0686 µg/µl, Aged: 0.0959 µg/µl, p< 0.0001) and pyridinoline cross-link content (Adult: 211.8 nmol/L, Aged: 490.0 nmol/L, p< 0.0001) compared to adult mice. Single cell RNA-sequencing analysis revealed a unique population of Periostin-positive (Postn+) cells from the fibro-adipogenic progenitor (FAP) lineage in both adult and aged plantaris muscles following mechanical overload. The Postn+ cells demonstrated unique and enriched expression of lysyl oxidase (Lox) with temporally exacerbated expression in aged muscle. We then hypothesized that Lox-mediated collagen crosslinking was a critical barrier to efficient ECM remodeling and muscle growth in aged animals. We generated mice allowing for the conditional knockout of Lox in a temporal manner in Postn+ cells (pLox-KO), and subjected pLox-KO and wild type (Lox-WT) aged mice (22-24mo) to mechanical overload. Following mechanical overload, pLox-KO mice showed a significant reduction in elastic stiffness (Lox-WT: 204.7 kPa, pLox-KO: 113.6 kPa, p=0.0254) and crosslinked collagen (Lox-WT: 0.1165 µg/µl, pLox-KO: 0.0801 µg/µl, p< 0.0001) that was associated with an improvement in muscle fiber size (Lox-WT: 1523 µm2, pLox-KO: 1732 µm2, p< 0.001) as compared to Lox-WT mice. These results suggest that the muscle ECM contributes to anabolic resistance of aged muscle, but not adult muscle. Thus, strategies to improve ECM composition and mechanics during MOV may help maintain or restore muscle plasticity with age. This work was supported by NIH awards R01AR072061 and R01AR083375. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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