Locomotor training with adjuvant testosterone preserves cancellous bone and promotes muscle plasticity in male rats after severe spinal cord injury

Abstract

Loading and testosterone may influence musculoskeletal recovery after spinal cord injury (SCI). Our objectives were to determine (a) the acute effects of bodyweight‐supported treadmill training (TM) on hindlimb cancellous bone microstructure and muscle mass in adult rats after severe contusion SCI and (b) whether longer‐term TM with adjuvant testosterone enanthate (TE) delivers musculoskeletal benefit. In Study 1, TM (40 min/day, 5 days/week, beginning 1 week postsurgery) did not prevent SCI‐induced hindlimb cancellous bone loss after 3 weeks. In Study 2, TM did not attenuate SCI‐induced plantar flexor muscles atrophy nor improve locomotor recovery after 4 weeks. In our main study, SCI produced extensive distal femur and proximal tibia cancellous bone deficits, a deleterious slow‐to‐fast fiber‐type transition in soleus, lower muscle fiber cross‐sectional area (fCSA), impaired muscle force production, and levator ani/bulbocavernosus (LABC) muscle atrophy after 8 weeks. TE alone (7.0 mg/week) suppressed bone resorption, attenuated cancellous bone loss, constrained the soleus fiber‐type transition, and prevented LABC atrophy. In comparison, TE+TM concomitantly suppressed bone resorption and stimulated bone formation after SCI, produced near‐complete cancellous bone preservation, prevented the soleus fiber‐type transition, attenuated soleus fCSA atrophy, maintained soleus force production, and increased LABC mass. 75% of SCI+TE+TM animals recovered voluntary over‐ground hindlimb stepping, while no SCI and only 20% of SCI+TE animals regained stepping ability. Positive associations between testosterone and locomotor function suggest that TE influenced locomotor recovery. In conclusion, short‐term TM alone did not improve bone, muscle, or locomotor recovery in adult rats after severe SCI, while longer‐term TE+TM provided more comprehensive musculoskeletal benefit than TE alone.

Contusion spinal cord injury upregulates p53 protein expression in rat soleus muscle at multiple timepoints but not key senescence cytokines

“…In this regard, others have reported that IL‐6 protein is released from soleus but not the predominantly fast‐glycolytic extensor digitorum longus (EDL) of mice, using an ex vivo assay, and that IL‐6 protein expression was primarily expressed in small oxidative fibers of the gastrocnemius and not in larger glycolytic fibers (Liang, Drazick, Gao, & Li, ). Furthermore, it should be noted that a profound slow‐oxidative to fast‐glycolytic fiber‐type shift occurs in the soleus in our moderate–severe contusion SCI model within the time frame of our current study (Yarrow, Kok, & Phillips, ) and it remains unclear whether this phenotypic change has any influence on our findings.…”

The Effects of Exercise and Activity-Based Physical Therapy on Bone after Spinal Cord Injury

“…Similarly, in rodent models of severe SCI, the use of dynamic histomorphometry has revealed that trabecular bone resorption persists at the distal femur and proximal tibia in the near absence of bone formation throughout the initial one to three-weeks post-SCI [ 44 , 52 , 53 , 54 , 55 , 56 , 57 ], when nearly all the trabecular bone loss occurs. Thereafter, trabecular bone formation renormalizes [ 58 , 59 ] and bone loss slows [ 52 ].…”

“…In this study, two-weeks of quadrupedal (q)BWSTT reversed the bone loss that resulted from cast immobilization but did not lessen bone loss that resulted directly from SCI. In a follow-up study, three-weeks of qBWSTT was also shown not to attenuate trabecular bone deterioration after SCI [ 59 ].…”

“…Preclinical SCI models can also be used to evaluate combinatory strategies to improve BMD. In this regard, several recent preclinical and clinical studies have assessed ABPTs combined with antiresorptive drugs, such as zoledronic acid [ 141 , 144 ] or testosterone [ 59 , 104 , 148 ], or bone anabolic drugs such as teriparatide [ 101 ], with varying success.…”

Conductive and injectable hyaluronic acid/gelatin/gold nanorod hydrogels for enhanced surgical translation and bioprinting

“…First, regenerative medicine may be needed to regenerate the axonal pathways, and second, rehabilitation approaches may be needed to promote functionality of the axons. Several in vivo studies 4,5 using regenerative rehabilitation have already produced better outcomes for nerve regeneration after SCI; however, there are few clinical trials for SCI using regenerative rehabilitation (e.g., cells + motor training [clinicaltrials.gov: NCT03979742, NCT03225625], scaffold + EES [NCT03966794]). Ultimately, there is a need for regenerative medicine approaches to be translated for use in the clinic and to be developed to complement and enhance rehabilitation approaches.…”