Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

Abstract

Spinal cord injury (SCI) results in rapid muscle loss. The mechanisms of muscle atrophy have been well-described but there is limited information specific to SCI. Exogenous molecular interventions to slow muscle atrophy in severe-to-complete SCI have been relatively ineffective and the wide-ranging physiologic response to SCI requires the search for novel therapeutic targets. Connexin hemichannels (CxHC) allow non-selective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising pre-clinical results in slowing atrophy during sepsis and dysferlinopathy. We administered 50 mg/kg/d of boldine to spinal cord transected mice beginning at day 3 post-injury. Tissue was collected 7 and 28 d post-injury and the gastrocnemius used for multiomic profiling. Boldine did not prevent body or muscle mass loss but attenuatee SCI-induced changes in the abundance of proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 d post-SCI. SCI resulted in the differential expression of ~7,700 and ~2,000 genes at 7 and 28 d, respectively, compared to sham animals, with enrichment for pathways associated with ribosome biogenesis, translation and oxidative phosphorylation. Boldine altered the expression of ~150 genes at 7 d and ~110 genes at 28 d post-SCI. Methylation analyses highlighted distinct patterns at both 7 and 28 d following SCI both with and without boldine. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it preserved or attenuated SCI-induced changes across the metabolome, transcriptome and methylome.

Boldine modulates glial transcription and functional recovery in a murine model of contusion spinal cord injury

“…While there are no reports of interactions between boldine and steroid hormone action it remains possible that boldine alters signaling via estrogen or androgen receptors or the rapid, steroid hormone receptor-independent, transient signaling elicited by steroid hormones at the cytoplasmic membrane of various cells including neurons (Estrada et al, 2006). Our recent analysis of the effects of boldine on the multiome of skeletal muscle at 7 or 28 days after spinal cord transection identified androgen signaling as being impacted in muscle by boldine (Potter et al, 2023). Further investigation is needed to understand the biological basis for the greater effects of boldine on locomotor function in males after spinal cord contusion.…”

Combined aerobic and resistance exercise training alters the spatial transcriptome of skeletal muscle in young adults

“…Skeletal muscle is a complex tissue containing, in addition to primary myofibers, numerous non-myofiber cell types and associated structures (e.g., neural, vascular, connective, and adipose tissues along with immune cells, stem cells, etc.). Traditional approaches to muscle transcriptomics have mostly relied on bulk sequencing of RNA isolated from whole tissue [6][7][8][9] or from single cell/nuclei isolated from the muscle environment [10][11][12] . While these data have been invaluable, they are incomplete as they lack important architectural information about the local cellular environment and origin of the RNA as the tissue adapts to exercise training.…”