Impact of muscle atrophy on bone metabolism and bone strength: implications for muscle-bone crosstalk with aging and disuse

Abstract

Bone fractures in older adults are often preceded by a loss of muscle mass and strength. Likewise, bone loss with prolonged bed rest, spinal cord injury, or with exposure to microgravity is also preceded by a rapid loss of muscle mass. Recent studies using animal models in the setting of hindlimb unloading or botulinum toxin (Botox) injection also reveal that muscle loss can induce bone loss. Moreover, muscle-derived factors such as irisin and leptin can inhibit bone loss with unloading, and knockout of catabolic factors in muscle such as the ubiquitin ligase Murf1 or the myokine myostatin can reduce osteoclastogenesis. These findings suggest that therapies targeting muscle in the setting of disuse atrophy may potentially attenuate bone loss, primarily by reducing bone resorption. These potential therapies not only include pharmacological approaches but also interventions such as whole-body vibration coupled with resistance exercise and functional electric stimulation of muscle.

Keywords: Irisin; Microgravity; Myostatin; Osteoclasts; Resistance training.

Figure 1

Graphs showing measures of cortical area (A; p<0.001 ANOVA) and cortical thickness (B; p<0.05 ANOVA) in men with grip strength values in the lowest (Q1) and highest (Q4) quartiles. Data from ref. [20]. C. Schematic showing the significant differences in bone cross-sectional shape of the radius among men in the lowest and highest quartiles of grip strength.

Figure 2

A. Histological sections of the distal femur stained for tartrate resistant acid phosphatase in normal mice (WT, left column) and mice lacking myostatin (MSTN KO, right column) after 7 days hindlimb unloading (SUSP). Arrows point to numerous osteoclasts on the subperiosteal surface in wild-type mice but not in myostatin-deficient mice after unloading. C=cortical bone, p=periosteum, med=medullary cavity. B. Quantification of osteoclast number per bone surface on the periosteum of ground control (CON) and tail-suspended (SUSP) normal (WT) and myostatin-deficient (MSTN KO) mice.

Figure 2

A. Histological sections of the distal femur stained for tartrate resistant acid phosphatase in normal mice (WT, left column) and mice lacking myostatin (MSTN KO, right column) after 7 days hindlimb unloading (SUSP). Arrows point to numerous osteoclasts on the subperiosteal surface in wild-type mice but not in myostatin-deficient mice after unloading. C=cortical bone, p=periosteum, med=medullary cavity. B. Quantification of osteoclast number per bone surface on the periosteum of ground control (CON) and tail-suspended (SUSP) normal (WT) and myostatin-deficient (MSTN KO) mice.

Figure 3

Relationship of muscle atrophy, and muscle hypertrophy, to myokines impacting bone resorption by osteoclasts (red) and bone formation by osteoblasts (blue). Myostatin expression and secretion is increased with unloading, increasing bone resorption. Follistatin is increased with muscle contraction and hypertrophy, suppressing myostatin-induced bone resorption. Follistatin and the myokine irisin, which is also increased with muscle contraction, can both directly inhibit osteoclastogenesis and irisin stimulates osteogenesis.