madman
Super Moderator
Abstract
Skeletal muscle atrophy is a hallmark of severe spinal cord injury (SCI) that is precipitated by neural insult and paralysis. Additionally, other factors may influence muscle loss, including systemic inflammation, low testosterone, low insulin-like growth factor (IGF)-1, and high-dose glucocorticoid treatment. The signaling cascades that drive SCI-induced muscle loss are common among most forms of disuse atrophy and include ubiquitin-proteasome signaling and others. However, differing magnitudes and patterns of atrophic signals exist after SCI versus other disuse conditions and are accompanied by endogenous inhibition of IGF1/PI3K/Akt signaling, which combines to produce exceedingly rapid atrophy. Several well-established anabolic agents, including androgens and myostatin inhibitors, display diminished ability to prevent SCI-induced atrophy, while ursolic acid and b2-agonists more effectively attenuate muscle loss. Strategies combining physical rehabilitation regimens to reload the paralyzed limbs with drugs targeting the underlying molecular pathways hold the greatest potential to improve muscle recovery after severe SCI.
Introduction
In the United States, ~80,000-120,000 individuals are living with a severe motor-complete spinal cord injury (SCI) [1], which induces immediate and permanent paralysis in muscles innervated below the spinal lesion. Rapid skeletal muscle atrophy is a hallmark of severe SCI that is precipitated by the neural insult and the resulting neuromuscular impairment, with 25-60% lower muscle cross-sectional area (CSA) and muscle fiber (f)CSA in paralyzed muscles 3-6 months post-injury [2]. Changes in the molecular signaling cascades that regulate muscle size are distinct after severe SCI, with muscle loss being more rapid than in other disuse conditions, such as hindlimb immobilization [3] or sciatic transection [4]. Therefore, pharmacologic strategies intending to limit SCI-induced muscle loss must target the initiating atrophy pathways in the paralyzed limbs, while also addressing systemic physiologic consequences of SCI that have the potential to exacerbate muscle loss and/or inhibit muscle recovery. This minireview provides overviews of the SCI muscle phenotype, the molecular signaling pathways, and secondary factors that influence muscle atrophy, and recent pharmacologic approaches to lessen muscle loss in the paralyzed limbs after severe SCI.
2. Pathophysiology of skeletal muscle loss following spinal cord injury
3. Pharmacologic approaches to ameliorate muscle atrophy after SCI
4. Androgens
Testosterone is the most abundant bioactive androgen within the circulation. Pharmacologic testosterone increases muscle mass in able-bodied hypogonadal men when administered in sufficient doses [21], either via direct androgen receptor engagement and/or indirectly via androgen-induced alterations in anabolic (e.g., IGF1/PI3K/Akt) or catabolic signaling (e.g., myostatin/ Smad-3) pathways [2]. In the 1950s, Cooper et al. [22] reported elevated urinary nitrogen excretion and a negative nitrogen balance that persisted for several months in persons with SCI and that high-dose testosterone (50-100 mg/day) normalized nitrogen balance by mitigating nitrogen excretion, suggesting that high-dose testosterone may limit muscle wasting after SCI. However, this possibility has yet to be verified, likely because high-dose testosterone produces several health risks, including prostate enlargement [23]. Alternatively, moderate-dose testosterone (5-10 mg/day for 12 months) was shown to increase whole body and lower extremity lean mass in a small cohort of hypogonadal men with chronic complete SCI [24], with improvements persisting for 6 months [25]. In contrast, low-dose testosterone (2-6 mg/day for 16 weeks) did not increase whole-body lean mass, lower extremity muscle CSA [26], or muscle fCSA [27] in eugonadal and hypogonadal men with chronic complete SCI. These small trials did not observe prostate enlargement nor reported any serious adverse events. In comparison, some preclinical SCI studies reported that high-dose testosterone increased the mass of the prostate and of the levator ani-bulbocavernosus (LABC) muscle (involved in sexual function) and various hindlimb muscles [2], while others have reported that testosterone did not increase muscle mass or fCSA in the paralyzed hindlimbs [28e31]. The reasons for these inconsistencies are unknown, although androgen receptor expression is greater than threefold higher in the prostate and LABC (androgen-responsive tissues) versus soleus [30] and other non-androgen-responsive hindlimb muscles [2]. Regardless, testosterone has been shown to suppress muscle FOXO1, MAFbx, MuRF1, and REDD1 expression and lessen the excess atrophy associated with methylprednisolone treatment in a rodent spinal transection model [17]. Moreover, testosterone attenuated gastrocnemius muscle loss after spinal transection, when given in combination with nandrolone (non-5a-reducible androgen), with muscle preservation being associated with reduced ACVR2B (myostatin receptor) expression and reduced nuclear content of Smad2/3 (downstream effectors of myostatin signaling) [31]. In a rodent severe SCI model, high-dose testosterone with finasteride (US Food and Drug Administration (FDA)-approved 5a-reductase inhibitor) also lessened prostate enlargement versus testosterone alone and did not impede androgen-induced LABC growth [32], indicating that the 5a reduction of testosterone mediates prostate growth but not muscle growth. However, these preclinical findings remain to be verified in clinical trials.
5. b2-Adrenergic agonists
6. Myostatin inhibitors
7. SS-31/Elamipretide
8. Natural products
9. Future directions
Activity-based physical therapies (ABPTs) have been used to combat muscle atrophy and the deleterious muscle phenotype that develops following SCI [2]. For example, both bodyweight-supported treadmill training (BWSTT) and neuromuscular electrical stimulation (NMES) are known to increase muscle CSA in persons with chronic complete SCI and to facilitate a fast glycolytic to slow-oxidative fiber-type conversion [2,5], although ABPT effectiveness wanes as injury severity increases and continual training is needed to maintain muscular gains. Given these limitations, it seems relevant to assess pharmacologic adjuvants combined with established ABPTs. For example, in a rodent severe SCI model high-dose testosterone combined with quadrupedal (q)BWSTT (40 min/day, 5/week) attenuated soleus fCSA atrophy prevented the soleus slow-to-fast fiber-type transition, and maintained isolated muscle force production is better than testosterone alone [28]. Similarly, in a rodent spinal transection model, a multimodal therapy involving high-dose testosterone with electrical stimulation (1.5 V, 40 Hz, 2 s:18 s on: off) suppressed MAFbx and MuRF1 expression better than testosterone alone and produced slightly better muscle recovery [29]. Moreover, in men with chronic complete SCI low-dose testosterone in combination with a 16- week NMES-based progressive resistance training protocol produced greater knee extensor CSA and fCSA than testosterone alone [26,27]. Collectively, these studies provide evidence that multimodal therapies combining ABPTs with pharmacologic adjuvants provide improved muscle recovery after severe SCI.
10. Conclusion
Numerous pharmacologic agents stimulate hypertrophy in fully innervated and loaded muscles. However, most anabolic agents display a diminished ability to lessen atrophy in the paralyzed limbs after severe SCI for yet to be identified reasons, although several possibilities exist. First, most anabolic drugs target specific signaling pathways but not the plethora of molecular changes in atrophic muscle after SCI, highlighting the need to elucidate the complexity of signaling pathways that drive SCI-induced muscle loss and to identify pharmaceuticals that target these pathways. Second, increased atrophy signaling coincides with reduced anabolic signaling after SCI, as detailed above, implying that effective drugs may need to suppress atrophy and simultaneously stimulate anabolic pathways, which has proven difficult in the absence of innervation and loading in the paralyzed limbs. Third, muscle atrophy occurs more rapidly after severe SCI than in other disuse conditions, suggesting that the ideal window to prevent muscle loss is limited. Given these possibilities, compounds that target the molecular signatures present in atrophic muscle after SCI appear to hold the greatest potential to lessen muscle loss and/or promote muscle recovery, especially when combined with established ABPTs that reload the paralyzed limbs.
Skeletal muscle atrophy is a hallmark of severe spinal cord injury (SCI) that is precipitated by neural insult and paralysis. Additionally, other factors may influence muscle loss, including systemic inflammation, low testosterone, low insulin-like growth factor (IGF)-1, and high-dose glucocorticoid treatment. The signaling cascades that drive SCI-induced muscle loss are common among most forms of disuse atrophy and include ubiquitin-proteasome signaling and others. However, differing magnitudes and patterns of atrophic signals exist after SCI versus other disuse conditions and are accompanied by endogenous inhibition of IGF1/PI3K/Akt signaling, which combines to produce exceedingly rapid atrophy. Several well-established anabolic agents, including androgens and myostatin inhibitors, display diminished ability to prevent SCI-induced atrophy, while ursolic acid and b2-agonists more effectively attenuate muscle loss. Strategies combining physical rehabilitation regimens to reload the paralyzed limbs with drugs targeting the underlying molecular pathways hold the greatest potential to improve muscle recovery after severe SCI.
Introduction
In the United States, ~80,000-120,000 individuals are living with a severe motor-complete spinal cord injury (SCI) [1], which induces immediate and permanent paralysis in muscles innervated below the spinal lesion. Rapid skeletal muscle atrophy is a hallmark of severe SCI that is precipitated by the neural insult and the resulting neuromuscular impairment, with 25-60% lower muscle cross-sectional area (CSA) and muscle fiber (f)CSA in paralyzed muscles 3-6 months post-injury [2]. Changes in the molecular signaling cascades that regulate muscle size are distinct after severe SCI, with muscle loss being more rapid than in other disuse conditions, such as hindlimb immobilization [3] or sciatic transection [4]. Therefore, pharmacologic strategies intending to limit SCI-induced muscle loss must target the initiating atrophy pathways in the paralyzed limbs, while also addressing systemic physiologic consequences of SCI that have the potential to exacerbate muscle loss and/or inhibit muscle recovery. This minireview provides overviews of the SCI muscle phenotype, the molecular signaling pathways, and secondary factors that influence muscle atrophy, and recent pharmacologic approaches to lessen muscle loss in the paralyzed limbs after severe SCI.
2. Pathophysiology of skeletal muscle loss following spinal cord injury
3. Pharmacologic approaches to ameliorate muscle atrophy after SCI
4. Androgens
Testosterone is the most abundant bioactive androgen within the circulation. Pharmacologic testosterone increases muscle mass in able-bodied hypogonadal men when administered in sufficient doses [21], either via direct androgen receptor engagement and/or indirectly via androgen-induced alterations in anabolic (e.g., IGF1/PI3K/Akt) or catabolic signaling (e.g., myostatin/ Smad-3) pathways [2]. In the 1950s, Cooper et al. [22] reported elevated urinary nitrogen excretion and a negative nitrogen balance that persisted for several months in persons with SCI and that high-dose testosterone (50-100 mg/day) normalized nitrogen balance by mitigating nitrogen excretion, suggesting that high-dose testosterone may limit muscle wasting after SCI. However, this possibility has yet to be verified, likely because high-dose testosterone produces several health risks, including prostate enlargement [23]. Alternatively, moderate-dose testosterone (5-10 mg/day for 12 months) was shown to increase whole body and lower extremity lean mass in a small cohort of hypogonadal men with chronic complete SCI [24], with improvements persisting for 6 months [25]. In contrast, low-dose testosterone (2-6 mg/day for 16 weeks) did not increase whole-body lean mass, lower extremity muscle CSA [26], or muscle fCSA [27] in eugonadal and hypogonadal men with chronic complete SCI. These small trials did not observe prostate enlargement nor reported any serious adverse events. In comparison, some preclinical SCI studies reported that high-dose testosterone increased the mass of the prostate and of the levator ani-bulbocavernosus (LABC) muscle (involved in sexual function) and various hindlimb muscles [2], while others have reported that testosterone did not increase muscle mass or fCSA in the paralyzed hindlimbs [28e31]. The reasons for these inconsistencies are unknown, although androgen receptor expression is greater than threefold higher in the prostate and LABC (androgen-responsive tissues) versus soleus [30] and other non-androgen-responsive hindlimb muscles [2]. Regardless, testosterone has been shown to suppress muscle FOXO1, MAFbx, MuRF1, and REDD1 expression and lessen the excess atrophy associated with methylprednisolone treatment in a rodent spinal transection model [17]. Moreover, testosterone attenuated gastrocnemius muscle loss after spinal transection, when given in combination with nandrolone (non-5a-reducible androgen), with muscle preservation being associated with reduced ACVR2B (myostatin receptor) expression and reduced nuclear content of Smad2/3 (downstream effectors of myostatin signaling) [31]. In a rodent severe SCI model, high-dose testosterone with finasteride (US Food and Drug Administration (FDA)-approved 5a-reductase inhibitor) also lessened prostate enlargement versus testosterone alone and did not impede androgen-induced LABC growth [32], indicating that the 5a reduction of testosterone mediates prostate growth but not muscle growth. However, these preclinical findings remain to be verified in clinical trials.
5. b2-Adrenergic agonists
6. Myostatin inhibitors
7. SS-31/Elamipretide
8. Natural products
9. Future directions
Activity-based physical therapies (ABPTs) have been used to combat muscle atrophy and the deleterious muscle phenotype that develops following SCI [2]. For example, both bodyweight-supported treadmill training (BWSTT) and neuromuscular electrical stimulation (NMES) are known to increase muscle CSA in persons with chronic complete SCI and to facilitate a fast glycolytic to slow-oxidative fiber-type conversion [2,5], although ABPT effectiveness wanes as injury severity increases and continual training is needed to maintain muscular gains. Given these limitations, it seems relevant to assess pharmacologic adjuvants combined with established ABPTs. For example, in a rodent severe SCI model high-dose testosterone combined with quadrupedal (q)BWSTT (40 min/day, 5/week) attenuated soleus fCSA atrophy prevented the soleus slow-to-fast fiber-type transition, and maintained isolated muscle force production is better than testosterone alone [28]. Similarly, in a rodent spinal transection model, a multimodal therapy involving high-dose testosterone with electrical stimulation (1.5 V, 40 Hz, 2 s:18 s on: off) suppressed MAFbx and MuRF1 expression better than testosterone alone and produced slightly better muscle recovery [29]. Moreover, in men with chronic complete SCI low-dose testosterone in combination with a 16- week NMES-based progressive resistance training protocol produced greater knee extensor CSA and fCSA than testosterone alone [26,27]. Collectively, these studies provide evidence that multimodal therapies combining ABPTs with pharmacologic adjuvants provide improved muscle recovery after severe SCI.
10. Conclusion
Numerous pharmacologic agents stimulate hypertrophy in fully innervated and loaded muscles. However, most anabolic agents display a diminished ability to lessen atrophy in the paralyzed limbs after severe SCI for yet to be identified reasons, although several possibilities exist. First, most anabolic drugs target specific signaling pathways but not the plethora of molecular changes in atrophic muscle after SCI, highlighting the need to elucidate the complexity of signaling pathways that drive SCI-induced muscle loss and to identify pharmaceuticals that target these pathways. Second, increased atrophy signaling coincides with reduced anabolic signaling after SCI, as detailed above, implying that effective drugs may need to suppress atrophy and simultaneously stimulate anabolic pathways, which has proven difficult in the absence of innervation and loading in the paralyzed limbs. Third, muscle atrophy occurs more rapidly after severe SCI than in other disuse conditions, suggesting that the ideal window to prevent muscle loss is limited. Given these possibilities, compounds that target the molecular signatures present in atrophic muscle after SCI appear to hold the greatest potential to lessen muscle loss and/or promote muscle recovery, especially when combined with established ABPTs that reload the paralyzed limbs.
