Exercise Protein CLCF1 Fights Age-Related Muscle and Bone Loss in Mice
A muscle-secreted protein boosted by exercise declines with age — restoring it in old mice reverses muscle weakness and bone loss.
Summary
Researchers identified CLCF1, a muscle-derived protein (myokine), as an exercise-induced factor that declines with aging in both humans and rodents. By analyzing human muscle transcriptome data and conducting experiments in aged male mice, they showed that restoring CLCF1 levels improved physical performance, glucose tolerance, and mitochondrial activity. CLCF1 also protected against age-related bone loss by simultaneously inhibiting osteoclasts (bone-breaking cells) and promoting osteoblasts (bone-building cells). Blocking CLCF1 abolished the musculoskeletal benefits of exercise training, confirming its central role as a mediator of exercise's positive effects on aging muscle and bone.
Detailed Summary
As we age, the musculoskeletal system deteriorates — muscles weaken (sarcopenia) and bones thin (osteoporosis) — and these conditions are deeply interrelated. Exercise is known to mitigate both, partly through myokines: signaling proteins secreted by muscle during physical activity. Yet how aging impairs the muscle's myokine-secreting capacity, and which specific factors mediate exercise's protective effects, has remained poorly understood.
This study set out to identify exercise-induced myokines diminished by aging. The researchers reanalyzed transcriptomic data from human skeletal muscle biopsies (young adults aged 24–25 vs. older adults aged 78–84) across multiple exercise conditions, screening 2,933 secreted-protein genes. Cardiotrophin-like cytokine factor 1 (CLCF1), a member of the IL-6 cytokine family that signals via gp130/LIFR/CNTFR receptors, emerged as a top candidate — upregulated by chronic resistance training in older adults but diminished at baseline with age. Multiple human exercise studies confirmed that resistance and high-intensity interval training acutely and chronically raised plasma CLCF1, while circulating levels were significantly lower in elderly versus young individuals at rest.
In cell-based models, AICAR (an AMPK activator mimicking exercise signals) and electrical pulse stimulation both increased CLCF1 expression in C2C12 myotubes, and high-intensity treadmill running raised muscle CLCF1 mRNA in rodents, confirming skeletal muscle as a primary source. Importantly, administering recombinant CLCF1 protein to aged male mice produced a striking suite of benefits: improved grip strength, treadmill endurance, glucose tolerance, and enhanced mitochondrial biogenesis and function in muscle tissue — mirroring the effects of exercise training. Mechanistically, CLCF1 activated JAK/STAT3 and PI3K/AKT/mTOR pathways in muscle, stimulating protein synthesis and reducing atrophy markers.
On the bone side, CLCF1 administration to aged mice preserved bone mineral density and microarchitecture. It suppressed osteoclastogenesis (bone resorption) by downregulating RANKL signaling, while promoting osteoblast differentiation and bone formation markers. Crucially, when CLCF1 activity was blocked in exercising aged mice — using a neutralizing antibody or receptor antagonism — the exercise-induced gains in both muscle function and bone quality were significantly abolished, establishing CLCF1 as a non-redundant mediator of exercise's musculoskeletal benefits.
These findings position CLCF1 as a promising therapeutic target for sarcopenia and osteoporosis, especially for individuals who cannot exercise adequately. However, the study was conducted exclusively in male mice, the human data are exploratory and cross-sectional in parts, and long-term safety and efficacy of exogenous CLCF1 administration in humans remain to be established.
Key Findings
- CLCF1 plasma levels decline with age in humans and are significantly elevated by resistance and high-intensity exercise.
- Recombinant CLCF1 in aged male mice improved grip strength, endurance, glucose tolerance, and mitochondrial activity.
- CLCF1 suppressed osteoclastogenesis and promoted osteoblast differentiation, protecting aged mice from bone loss.
- Blocking CLCF1 abolished the musculoskeletal benefits of exercise training in aged mice.
- CLCF1 activates JAK/STAT3 and PI3K/AKT/mTOR pathways in muscle, driving anabolic and mitochondrial responses.
Methodology
The study combined reanalysis of human skeletal muscle transcriptomics (GSE28422, young vs. elderly across exercise conditions), multiple human plasma CLCF1 cohort studies, in vitro myotube models (AICAR and electrical pulse stimulation), and in vivo experiments in aged male mice using recombinant CLCF1 administration and neutralizing antibody blockade.
Study Limitations
All in vivo experiments were conducted only in male mice, limiting generalizability to females and humans. Human plasma CLCF1 data are exploratory, with small cohorts and varying exercise protocols. Long-term safety, optimal dosing, and efficacy of exogenous CLCF1 in humans have not been evaluated.
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