Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism

Abstract

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-β, and E4BP4. PPARγ and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.

Impact of Melatonin on Skeletal Muscle and Exercise

“…These data agreed with Manickam et al's study, which demonstrated dysbiosis in pathogen-free mice treated with the antibiotic metronidazole producing scarce gastrocnemius muscle mass, abnormal activation of atrophy genes, and insulin resistence [209]. Conversely, fecal transplantation of old human subjects with high physical performance, called high functioning, in germ-free mice induced a peculiar microflora rich in Prevotella and Barnesiella species and developed more grip strength [210].…”

The Role of the Gut Microbiome on Skeletal Muscle Mass and Physical Function: 2019 Update

“…In support of this, the muscle mass/body weight ratio was reduced in young GFM, and colonization of GFM with fecal samples from age-matched conventionally raised mice restored the muscle mass/body weight ratio (Lahiri et al, 2019). Similarly, in antibiotic-treated young mice, muscle mass was reduced (Manickam et al, 2018;Nay et al, 2019;Okamoto et al, 2019) without a corresponding change in body weight (Manickam et al, 2018;Okamoto et al, 2019), thereby resulting in a decreased muscle mass/body weight ratio (Nay et al, 2019). In addition, muscle mass and the muscle mass/body weight ratio were increased following natural microbiota seeding in antibiotic-treated mice (Nay et al, 2019).…”

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

“…However, conventionalized mice treated with metronidazole, leading to Proteobacteria in mouse feces, perpetuated changes in the metabolic and circadian profiles of the gastrocnemius muscle. Expression of PPAR-g and its target gene adiponectin as well as circadian clock genes Per2, Cry2, Ror-b, and E4BP4 were all up-regulated in the skeletal muscle of the treated SPF mice but not in GF mice (242). How this impacts mice physiologically and metabolically is yet to be elucidated.…”

“…4). Conventionalized mice treated with metronidazole, a class of antimicrobial drug that targets anaerobic bacteria, demonstrated the significant impact of an altered gut microbiota on the skeletal muscle (242). Metronidazole treatment led to an increase in Proteobacteria in mouse feces.…”