Preclinical assessment of the selective androgen receptor modulator RAD140 to increase muscle mass and bone mineral density

Abstract

Selective androgen receptor modulators (SARMs) are important hypertrophic molecules that are potential treatments for many types of myopathy and osteopathy. This study aimed to determine if the SARM RAD140 had additive effects on muscle hypertrophy when combined with the functional overloading (FO) of the plantaris muscle. Male, Sprague-Dawley rats (n = 10 rats/group) were randomly selected into one of four treatment groups: (1) RAD140-FO, (2) RAD140-Control, (3) Vehicle-Control, or (4) Vehicle-FO. RAD140 groups received drugs through drinking water, and control groups received only Vehicle (methylcellulose). Standard rat chow and water were provided ad libitum. Muscle weights of the triceps-surae group and muscle fiber cross-sectional area (CSA) were measured. Muscle weight analysis showed a marked increase in RAD140-FO groups but was not statistically different from the Vehicle-FO group. CSA results indicated similar findings; however, RAD140-Control showed significantly elevated CSA compared to Vehicle-Control. The tibial microarchitecture was analyzed using micro computed tomography. RAD140 did not impact cortical or trabecular bone structural morphometric properties following 14 days of treatment. The data presented here show the potential of RAD140 to stimulate muscle hypertrophy in young healthy rats.

Keywords: RAD140; SARM; cross‐sectional area; functional overload; hypertrophy; skeletal muscle.

FIGURE 1

(a) Schematic of the overall study design—each animal received a functional overload surgery by gastrocnemius bisection and a contralateral sham surgery as control. Half the animals were treated with RAD140 + 0.5% methylcellulose (RAD140) and half with control 0.5% methylcellulose (0.5 MC) as control in their daily water intake. All groups were extensively evaluated for functional changes at the end of the 14‐day study (b) Relative change in body weight plot highlighting the comparison of post‐intervention body weights of 0.5% methylcellulose and RAD140 treatment groups ± SD. The groups were not statistically different (ns). (c) Average daily water consumption (gm) per cage by treatment group ± SD. Statistical significance is indicated by the p value for water consumption.

FIGURE 2

(a) Representative histology of rat plantaris muscles: RAD140 + 0.5% methylcellulose (RAD140) and vehicle 0.5% methylcellulose (0.5 MC) from the functional overloaded (FO) limb or the contralateral control (Control). Magnification bar indicates 100 μm. Box and whisker plots illustrating the (b) plantaris cross‐sectional area (μm²), normalized weights of the (c) plantaris and (d) soleus muscles (mg/gm of total body weight) at study termination, where the limits of the box are the upper and lower quartiles, the whiskers are the upper and lower extremes, and the line within the box is at the median. Statistical significance is indicated by the p values for the comparisons; ns indicates a nonsignificant difference.

FIGURE 3

Representative microCT reconstructions of the (a) diaphyseal cortical bone and (e) epiphyseal trabecular bone from the tibia for each treatment group. The cortical (b) bone volume fraction (BV/TV) (%), (c) bone mineral density (grayscale AU), and (d) polar mass moment of inertia (MMI) (mm⁴) were compared between groups. Trabecular morphometry was conducted by computing the trabecular (f) bone volume fraction (BV/TV) (%), (g) bone surface to volume ratio (BS/BV) (mm⁻¹), (h) connectivity density (mm⁻³), (i) trabecular spacing (Tb.Sp.) (μm), (j) trabecular number (Tb.N.) (1/μm), and (k) trabecular thickness (Tb.Th.) (μm). For the box and whisker plots, the limits of the box represent the upper and lower quartiles, the whiskers are the upper and lower extremes, and the line within the box is at the median. No significant volumetric, density, or morphometric differences were observed between treatment groups.