Lumbar spine pathology is a complex and multifactorial condition associated with degenerative changes in the lumbar spinal muscles (multifidus and erector spinae) that are easily observable using conventional imaging techniques, and highly associated with poor surgical and nonsurgical outcomes. Although muscle degeneration is ubiquitous in this patient population, the underlying genetic and cellular mechanisms are not well understood, especially in relation to disease progression in humans. Therefore, we examined gene expression of 42 functionally important genes from relevant adipogenic/metabolic, atrophic, fibrogenic, inflammatory, and myogenic gene pathways by obtaining intraoperative multifidus muscle biopsies from patients undergoing surgery for lumbar spine pathology. Multifidus muscle morphology was examined at biopsy side and vertebral level using T2-weighted magnetic resonance imaging and bi-gaussian distribution to determine total multifidus cross-sectional area, cross-sectional area of muscle and fat, and fat fraction of the multifidus, both pre-operatively and 6 months post-operatively. These measures were used to investigate the relationships between gene expression patterns, whole muscle health (size and quality), and post-operative recovery. We found that fibrogenic (COL3A1) and adipogenic/metabolic genes (PPARD) were related to pre-operative muscle quality, and myogenic genes (mTOR) were related to pre-operative muscle size. Additionally, we found trends for relationships between inflammatory (TNF-a) genes and muscle loss after surgery, and fibrogenic genes (TIMP1, TIMP3) and muscle growth after surgery. These findings provide insight into important pathways associated with muscle health and adaptation in the presence of lumbar spine pathology and establish a foundation for future research in preventing muscle degenerative changes before and after surgery.