• Department of Computer Science, Vanderbilt University, Nashville, Tennessee.
• Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
• Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee.
• Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee.
• Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
• Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

RATIONALE: Skeletal muscle fat infiltration progresses with aging and is worsened among individuals with a history of cigarette smoking. Many negative impacts of smoking on muscles are likely reversible with smoking cessation.

OBJECTIVES: To determine if the progression of skeletal muscle fat infiltration with aging is altered by smoking cessation among lung cancer screening participants.

METHODS: This was a secondary analysis based on the National Lung Screening Trial. Skeletal muscle attenuation in Hounsfield unit (HU) was derived from the baseline and follow-up low-dose CT scans using a previously validated artificial intelligence algorithm. Lower attenuation indicates greater fatty infiltration. Linear mixed-effects models were constructed to evaluate the associations between smoking status and the muscle attenuation trajectory.

MEASUREMENTS AND MAIN RESULTS: Of 19,019 included participants (age: 61 years, 5 [SD]; 11,290 males), 8,971 (47.2%) were actively smoking cigarettes. Accounting for body mass index, pack-years, percent emphysema, and other confounding factors, actively smoking predicted a lower attenuation in both males (β₀ =-0.88 HU, P<.001) and females (β₀ =-0.69 HU, P<.001), and an accelerated muscle attenuation decline-rate in males (β₁=-0.08 HU/y, P<.05). Age-stratified analyses indicated that the accelerated muscle attenuation decline associated with smoking likely occurred at younger age, especially in females.

CONCLUSIONS: Among lung cancer screening participants, active cigarette smoking was associated with greater skeletal muscle fat infiltration in both males and females, and accelerated muscle adipose accumulation rate in males. These findings support the important role of smoking cessation in preserving muscle health.