Metformin improves skeletal muscle and physical capacity by stabilizing neuromuscular junction in older adults

Metformin is an anti-diabetic drug with protective effects on skeletal muscle and physical capacity. However, the relevant mechanisms of action on skeletal muscle remain poorly understood. We investigated the potential contribution of neuromuscular junction (NMJ) degradation to skeletal muscle and physical capacity in geriatric men taking metformin.

We recruited geriatric men for placebo (Age=73.1 ± 4.2 years, n = 70) and metformin (Age=70.1 ± 4.5 years, n = 62) groups. The patients in the metformin group received 1700 mg of metformin twice a day for 16 weeks. We measured plasma c-terminal agrin-fragment-22 (CAF22) and neurofilament light chain (NfL) as markers of neuromuscular junction (NMJ) degradation and neurodegeneration, respectively, with relevance to handgrip strength (HGS) and short physical performance battery (SPPB; a marker of physical capacity) in older adults taking metformin. These findings were associated with reduced oxidative stress in the metformin group.

At baseline, both groups had similar HGS, gait speed, SPPB scores, and plasma biochemistry. Metformin improved HGS, gait speed, and cumulative SPPB scores in geriatric men (all p < 0.05). Metformin also reduced plasma CAF22 and NfL levels when compared to baseline. Similar observations were not found in the placebo group. Correlation analysis revealed significant correlations of plasma CAF22 with HGS, gait speed, and cumulative SPPB scores in the metformin group. These observations were associated with reduced oxidative stress in the metformin group.

Altogether, the restorative effects of metformin on skeletal muscle and physical capacity involve NMJ stabilization. Our data is clinically relevant for geriatric men with functional disabilities.