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The Bone and Mitochondria Connection

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Bone is a living tissue that not only mechanically supports the body and protects vital organs, but also produces blood cells, stores minerals, and impacts endocrine regulation. As a result of aging, hormonal imbalances, nutrient deficiencies/insufficiencies, or the frequent use of certain medications, the bone remodeling cycle may become unbalanced, with bone resorption rates outpacing formation. Per recent statistics, the prevalence of osteoporosis at either the femoral neck, lumbar spine, or both among US adults aged 50 or older is 12.6%, while prevalence of low bone mass (i.e., osteopenia, a precursor for osteoporosis) for the same population is 43.1%.1 An important component of bone health is skeletal muscle. Additionally, age-related degradation of muscle mass is a continuous process, with some studies suggesting a reduction in lean muscle starting as early as age 30.2

Bone-Muscle Unit: Crosstalk, Osteosarcopenia, & the Role of Mitochondria

Evolving research supports the concept of the bone-muscle unit that engages in a crosstalk that involves molecules secreted by both tissues working together toward homeostasis.3,4 While osteoporosis is characterized by low bone mass and deterioration of bone tissue, sarcopenia is a progressive decline of muscle mass with loss of strength or physical performance. Growing evidence indicates that both disorders share many common biological pathways.3,4 In fact, the newly identified age-related musculoskeletal syndrome termed “osteosarcopenia” highlights the pathologic connections between simultaneous bone and muscle disorders. Osteosarcopenia is characterized by porous and fragile bone as well as low muscle mass and function4,5 and contributes to an increased risk of falls, fracture, and mortality.6

Mitochondria play an essential role in the health of the bone-muscle unit. Mitochondrial function and quantity are important in the maintenance of osteoblasts and osteoclasts in bone7 and for optimal function of myocytes in muscle.8 A recent animal study focusing on mitochondrial performance suggests that mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age-related bone loss.9 Related to overall muscle aging, mitochondria are central regulators.2 Specifically, the loss of mitochondrial integrity in myocytes has been recognized as a potential factor in age-related muscle degeneration.8

To address musculoskeletal health as we age, can optimizing mitochondrial function positively impact both bone quality and muscle mass or even reverse age-related bone and muscle disorders.

Connecting Musculoskeletal & Mitochondrial Health

Cellular senescence has been implicated in the progressive, age-related loss of function across various body tissues, including muscle and bone,10 and the quality of mitochondrial performance is a key component of senescence.8 Impaired energy metabolism and dysregulated mitochondrial homeostasis contribute to the negative impact of senescence. Senescent cells accumulate dysfunctional mitochondria, increasing reactive oxygen species (ROS) production.10,11 In addition, while continuing research will help to elucidate the exact mechanisms involved, mitophagy, the selective cellular recycling of mitochondria more generally known as autophagy, is reduced in senescent cells.11

In the described environment of sub-optimal mitochondrial quality and function, musculoskeletal health is negatively impacted. For example:

  • Mitochondrial bioenergetics and quality control systems regulate stem cells in bone homeostasis. Increasing evidence indicates that compromised energy metabolism and oxidative stress contribute to age-related stem cell dysfunction in bone.12
  • Mitophagy is suggested to play a vital role in the proliferation, differentiation, and function of osteoblasts and osteoclasts. Dysregulation of mitophagy may promote damaged mitochondria and potentially induce apoptosis of osteoblasts or osteoclastogenesis in bone disorders.7
  • Mitochondrial quality plays an important role in maintaining muscle health. Dysfunctional mitophagy, increased ROS production, reduced mitochondrial biogenesis, and increased mitochondrial apoptotic susceptibility are all potentially linked to age-related muscle atrophy and sarcopenia.2

Animal studies suggest that treatments specifically targeting mitochondrial dysfunction hold promise for improving musculoskeletal function during aging.10 A 2020 animal study investigated the beneficial effect of sodium butyrate, a representative short-chain fatty acid, on mitochondrial pathways and function.13 Results indicated that the sodium butyrate promoted mitochondrial antioxidant enzymes and energy metabolism, preserved bone microstructure and calcium homeostasis, and activated bone metabolism, reversing bone loss.13 Other studies have suggested that exercise increases levels of PGC-1alpha, which regulates mitochondrial biogenesis and attenuates the loss of skeletal muscle mass through the PGC-1alpha/SIRT1 signaling pathway.14

Clinical Applications

Lifestyle treatment strategies help to support musculoskeletal health. Research studies suggest that an anti-inflammatory diet,15 exercise,16 and supplements such as omega-3 fatty acids17 and probiotics18,19 may positively impact bone density and quality. Recommended therapeutic approaches for patients with sarcopenia include appropriate exercise interventions that help to attenuate muscle loss and rebuild muscle mass.20,21 Additional treatment components that enhance muscle strength may include increased quality proteins22 and vitamin D23 or omega-3 fatty acid24 supplementations. Targeting mitochondrial dysfunctions and boosting mitochondrial health through lifestyle treatments may also help to address both bone and muscle disorders.

Therapeutic food plans such as IFM’s Mitochondrial Food Plan use nutrition to support mitochondrial biogenesis for improved energy production. In addition, studies suggest that intermittent fasting routines, if appropriate for a patient’s personalized nutrition strategy, may positively impact mitochondrial function, enhancing energy metabolism and overall health.25,26 Exercise is another therapeutic approach to support mitochondria, promoting increased mitochondrial content, improving respiratory capacity of each mitochondrion, and reducing ROS production.27 A 2021 review investigated how different exercise modalities potentially reverse age-related changes in skeletal muscle mitochondria.28 The review found that endurance and resistance training separately and combined have suggested benefit for mitochondrial aging and muscle disorders.28 Specifically:

  • Resistance training maintains and improves mobility, strength, and movement, preserving skeletal muscle function.28
  • Endurance training improves energy metabolism, metabolic flexibility, and muscle quality.28
  • Combined training may combine these noted benefits to bolster mitochondrial performance and quality to preserve the energetic and functional health of aging skeletal muscle.28

Research on how mitochondrial function impacts musculoskeletal health and the aging process continues to evolve. Learn more about optimizing mitochondria through personalized treatment strategies at IFM’s Bioenergetics Advanced Practice Module (APM).

Learn More About Mitochondrial Function

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References

  1. Sarafrazi N, Wambogo EA, Shepherd JA. Osteoporosis or low bone mass in older adults: United States, 2017-2018. Centers for Disease Control and Prevention, National Center for Health Statistics. Published March 2021. Accessed May 17, 2021. https://www.cdc.gov/nchs/products/databriefs/db405.htm
  2. Wiedmer P, Jung T, Castro JP, et al. Sarcopenia – molecular mechanisms and open questions. Ageing Res Rev. 2021;65:101200. doi:10.1016/j.arr.2020.101200
  3. Reginster JY, Beaudart C, Buckinx F, Bruyère O. Osteoporosis and sarcopenia: two diseases or one? Curr Opin Clin Nutr Metab Care. 2016;19(1):31-36. doi:10.1097/MCO.0000000000000230
  4. He C, He W, Hou J, et al. Bone and muscle crosstalk in aging. Front Cell Dev Biol. 2020;8:585644. doi:10.3389/fcell.2020.585644
  5. Kirk B, Miller S, Zanker J, Duque G. A clinical guide to the pathophysiology, diagnosis and treatment of osteosarcopenia. Maturitas. 2020;140:27-33. doi:10.1016/j.maturitas.2020.05.012
  6. Teng Z, Zhu Y, Teng Y, et al. The analysis of osteosarcopenia as a risk factor for fractures, mortality, and falls. Osteoporos Int. Published online April 20, 2021. doi:10.1007/s00198-021-05963-x
  7. Wang S, Deng Z, Ma Y, et al. The role of autophagy and mitophagy in bone metabolic disorders. Int J Biol Sci. 2020;16(14):2675-2691. doi:10.7150/ijbs.46627
  8. Ferri E, Marzetti E, Calvani R, Picca A, Cesari M, Arosio B. Role of age-related mitochondrial dysfunction in sarcopenia. Int J Mol Sci. 2020;21(15):5236. doi:10.3390/ijms21155236
  9. Dobson PF, Dennis EP, Hipps D, et al. Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Sci Rep. 2020;10(1):11643. doi:10.1038/s41598-020-68566-2
  10. Habiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: implications for musculoskeletal ageing. Free Radic Biol Med. 2019;132:3-10. doi:10.1016/j.freeradbiomed.2018.10.417
  11. Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine. 2017;21:7-13. doi:10.1016/j.ebiom.2017.03.020
  12. Zheng CX, Sui BD, Qiu XY, Hu CH, Jin Y. Mitochondrial regulation of stem cells in bone homeostasis. Trends Mol Med. 2020;26(1):89-104. doi:10.1016/j.molmed.2019.04.008
  13. Tang X, Ma S, Li Y, et al. Evaluating the activity of sodium butyrate to prevent osteoporosis in rats by promoting osteal GSK-3?/Nrf2 signaling and mitochondrial function. J Agric Food Chem. 2020;68(24):6588-6603. doi:10.1021/acs.jafc.0c01820
  14. Mankhong S, Kim S, Moon S, Kwak HB, Park DH, Kang JH. Experimental models of sarcopenia: bridging molecular mechanism and therapeutic strategy. Cells. 2020;9(6):1385. doi:10.3390/cells9061385
  15. Malmir H, Saneei P, Larijani B, Esmaillzadeh A. Adherence to Mediterranean diet in relation to bone mineral density and risk of fracture: a systematic review and meta-analysis of observational studies. Eur J Nutr. 2018;57(6):2147-2160. doi:10.1007/s00394-017-1490-3
  16. Hettchen M, von Stengel S, Kohl M, et al. Changes in menopausal risk factors in early postmenopausal osteopenic women after 13 months of high-intensity exercise: the randomized controlled ACTLIFE-RCT. Clin Interv Aging. 2021;16:83-96. doi:10.2147/CIA.S283177
  17. Shen D, Zhang X, Li Z, Bai H, Chen L. Effects of omega-3 fatty acids on bone turnover markers in postmenopausal women: systematic review and meta-analysis. Climacteric. 2017;20(6):522-527. doi:10.1080/13697137.2017.1384952
  18. Lambert MNT, Thybo CB, Lykkeboe S, et al. Combined bioavailable isoflavones and probiotics improve bone status and estrogen metabolism in postmenopausal osteopenic women: a randomized controlled trial. Am J Clin Nutr. 2017;106(3):909-920. doi:10.3945/ajcn.117.153353
  19. Nilsson AG, Sundh D, Backhed F, Lorentzon M. Lactobacillus reuterireduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med. 2018;284(3):307-317. doi:10.1111/joim.12805
  20. Dent E, Morley JE, Cruz-Jentoft AJ, et al. International Clinical Practice Guidelines for Sarcopenia (ICFSR): screening, diagnosis and management. J Nutr Health Aging. 2018;22(10):1148-1161. doi:10.1007/s12603-018-1139-9
  21. Barajas-Galindo DE, González Arnaiz E, Ferrero Vicente P, Ballesteros-Pomar MD. Effects of physical exercise in sarcopenia. A systematic review. Endocrinol Diabetes Nutr. 2021;68(3):159-169. doi:10.1016/j.endinu.2020.02.010
  22. Granic A, Dismore L, Hurst C, Robinson SM, Sayer AA. Myoprotective whole foods, muscle health and sarcopenia: a systematic review of observational and intervention studies in older adults. Nutrients. 2020;12(8):2257. doi:10.3390/nu12082257
  23. Gkekas NK, Anagnostis P, Paraschou V, et al. The effect of vitamin D plus protein supplementation on sarcopenia: a systematic review and meta-analysis of randomized controlled trials. Maturitas. 2021;145:56-63. doi:10.1016/j.maturitas.2021.01.002
  24. Huang YH, Chiu WC, Hsu YP, Lo YL, Wang YH. Effects of omega-3 fatty acids on muscle mass, muscle strength and muscle performance among the elderly: a meta-analysis. Nutrients. 2020;12(12):3739. doi:10.3390/nu12123739
  25. Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. PLoS One. 2018;13(5):e0195912. doi:10.1371/journal.pone.0195912
  26. Madkour MI, El-Serafi AT, Jahrami HA, et al. Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT 1, SIRT3) gene expressions in subjects with overweight and obesity. Diabetes Res Clin Pract. 2019;155:107801. doi:10.1016/j.diabres.2019.107801
  27. Memme JM, Erlich AT, Phukan G, Hood DA. Exercise and mitochondrial health. J Physiol. 2021;599(3):803-817. doi:10.1113/JP278853
  28. Harper C, Gopalan V, Goh J. Exercise rescues mitochondrial coupling in aged skeletal muscle: a comparison of different modalities in preventing sarcopenia. J Transl Med. 2021;19(1):71. doi:10.1186/s12967-021-02737-1

 

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