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Explore the mechanisms underpinning mitochondrial conditions at the upcoming Bioenergetics Advanced Practice Module (APM). See full program details

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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. The prevalence of osteoporosis worldwide is estimated at 18.3%.¹ In the US, 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%.²

An important component of bone health is the health of skeletal muscle. Age-related degradation of muscle mass is a continuous process, with some studies suggesting a reduction in lean muscle starting as early as age 30,³ which has potential consequences for bone health.

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.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.⁴ In fact, the age-related musculoskeletal syndrome termed “osteosarcopenia” highlights the pathologic connections between simultaneous bone and muscle disorders.⁵ Osteosarcopenia is characterized by porous and fragile bone as well as low muscle mass and function^4,6 and contributes to an increased risk of falls, fracture, and mortality.⁷

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 bone^8,9 and for the function of myocytes in muscle.¹⁰ A recent animal study focusing on mitochondrial performance suggests that mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age-related bone loss.¹¹ Related to overall muscle aging, mitochondria are central regulators.³ Specifically, the loss of mitochondrial integrity in myocytes has been recognized as a potential factor in age-related muscle degeneration.^10,12

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? In the following video, Lisa (Perry) Portera, DC, IFMCP, discusses how the health of mitochondria impacts bone and muscle.

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,¹³ and the quality of mitochondrial performance is a key component of senescence.¹⁰ 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.¹⁴ 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.¹⁴

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.¹⁵
• 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.^8,16
• 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.³

Animal studies suggest that treatments specifically targeting mitochondrial dysfunction hold promise for improving musculoskeletal function during aging.¹³ A 2020 animal study investigated the beneficial effect of sodium butyrate, a representative short-chain fatty acid, on mitochondrial pathways and function.¹⁷ 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.¹⁷ 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.¹⁸

Clinical Applications – Bone & Muscle Health

Lifestyle treatment strategies help to support musculoskeletal health. Research studies suggest that an anti-inflammatory diet,¹⁹ exercise,²⁰ and supplements such as omega-3 fatty acids²¹ and probiotics^22,23 may positively impact bone health. Recommended therapeutic approaches for patients with sarcopenia include appropriate exercise interventions that help to attenuate muscle loss and rebuild muscle mass.^24-26 Additional treatment components that may enhance muscle strength may include increased quality proteins and vitamin D^27,28 or omega-3 fatty acid²⁹ supplementations.

Targeting mitochondrial dysfunctions and boosting mitochondrial health through lifestyle treatments may also help to address both bone and muscle health. In general, plant-based nutrients may be supportive of mitochondrial biogenesis and function.^30,31 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 function.^32,33 Exercise is another therapeutic approach to support mitochondria, promoting increased mitochondrial biogenesis and density, as well as improving function and oxidative capacity.^34,35

A 2021 review of clinical trials and animal-based models investigated how different exercise modalities potentially reverse age-related changes in skeletal muscle mitochondria.³⁶ The review found that endurance and resistance training, separately and combined, have suggested benefit for mitochondrial aging and muscle disorders.³⁶ Specifically:

• Resistance training may help maintain and improve mobility, strength, and movement, preserving skeletal muscle function.³⁶
• Endurance training may help improve energy metabolism, metabolic flexibility, and muscle quality.³⁶
• Combined training may combine these noted benefits to bolster mitochondrial performance and quality to preserve the energetic and functional health of aging skeletal muscle.³⁶

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

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References

1. Salari N, Ghasemi H, Mohammadi L, et al. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609. doi:1186/s13018-021-02772-0
2. Sarafrazi N, Wambogo EA, Shepherd JA. Osteoporosis or low bone mass in older adults: United States, 2017-2018. NCHS Data Brief. 2021;(405):1-8. https://www.cdc.gov/nchs/products/databriefs/db405.htm
3. Wiedmer P, Jung T, Castro JP, et al. Sarcopenia – molecular mechanisms and open questions. Ageing Res Rev. 2021;65:101200. doi:1016/j.arr.2020.101200
4. He C, He W, Hou J, et al. Bone and muscle crosstalk in aging. Front Cell Dev Biol. 2020;8:585644. doi:3389/fcell.2020.585644
5. Polito A, Barnaba L, Ciarapica D, Azzini E. Osteosarcopenia: a narrative review on clinical studies. Int J Mol Sci. 2022;23(10):5591. doi:3390/ijms23105591
6. 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:1016/j.maturitas.2020.05.012
7. Chen S, Xu X, Gong H, et al. Global epidemiological features and impact of osteosarcopenia: a comprehensive meta-analysis and systematic review. J Cachexia Sarcopenia Muscle. 2024;15(1):8-20. doi:1002/jcsm.13392
8. 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:7150/ijbs.46627
9. Yan C, Shi Y, Yuan L, et al. Mitochondrial quality control and its role in osteoporosis. Front Endocrinol (Lausanne). 2023;14:1077058. doi:3389/fendo.2023.1077058
10.  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:3390/ijms21155236
11.  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:1038/s41598-020-68566-2
12.  Sautchuk R Jr, Eliseev RA. Cell energy metabolism and bone formation. Bone Rep. 2022;16:101594. doi:1016/j.bonr.2022.101594
13.  Habiballa L, Salmonowicz H, Passos JF. Mitochondria and cellular senescence: implications for musculoskeletal ageing. Free Radic Biol Med. 2019;132:3-10. doi:1016/j.freeradbiomed.2018.10.417
14.  Ali T, Hussain F, Kayani HUR, Naeem M, Anjum F. The role of mitochondria and mitophagy in cell senescence. Adv Protein Chem Struct Biol. 2023;136:93-115. doi:1016/bs.apcsb.2023.03.001
15.  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:1016/j.molmed.2019.04.008
16.  Zeng Z, Zhou X, Wang Y, et al. Mitophagy—a new target of bone disease. Biomolecules. 2022;12(10):1420. doi:3390/biom12101420
17.  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:1021/acs.jafc.0c01820
18.  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:3390/cells9061385
19.  Zheng X, Li W, Yan Y, Su Z, Huang X. Association between the Dietary Inflammatory Index and fracture risk in older adults: a systematic review and meta-analysis. J Int Med Res. 2024;52(5):3000605241248039. doi:1177/03000605241248039
20.  Mohebbi R, Shojaa M, Kohl M, et al. Exercise training and bone mineral density in postmenopausal women: an updated systematic review and meta-analysis of intervention studies with emphasis on potential moderators. Osteoporos Int. 2023;34(7):1145-1178. doi:1007/s00198-023-06682-1
21.  Abdelhamid A, Hooper L, Sivakaran R, Hayhoe RPG, Welch A; PUFAH Group. The relationship between omega-3, omega-6 and total polyunsaturated fat and musculoskeletal health and functional status in adults: a systematic review and meta-analysis of RCTs. Calcif Tissue Int. 2019;105(4):353-372. doi:1007/s00223-019-00584-3
22.  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:3945/ajcn.117.153353
23.  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:1111/joim.12805
24.  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:1007/s12603-018-1139-9
25.  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:1016/j.endinu.2020.02.010
26.  Heo SJ, Jee YS. Intensity-effects of strengthening exercise on thigh muscle volume, pro- or anti-inflammatory cytokines, and immunocytes in the older adults: a randomized controlled trial.?Arch Gerontol Geriatr. 2024;116:105136. doi:1016/j.archger.2023.105136
27.  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:3390/nu12082257
28.  Cheng SH, Chen KH, Chen C, Chu WC, Kang YN. The optimal strategy of vitamin D for sarcopenia: a network meta-analysis of randomized controlled trials. Nutrients. 2021;13(10):3589. doi:3390/nu13103589
29.  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:3390/nu12123739
30.  Chodari L, Dilsiz Aytemir M, Vahedi P, et al. Targeting mitochondrial biogenesis with polyphenol compounds. Oxid Med Cell Longev. 2021;2021:4946711. doi:1155/2021/4946711
31.  Mthembu SXH, Dludla PV, Ziqubu K, et al. The potential role of polyphenols in modulating mitochondrial bioenergetics within the skeletal muscle: a systematic review of preclinical models. Molecules. 2021;26(9):2791. doi:3390/molecules26092791
32.  Zhao Y, Jia M, Chen W, Liu Z. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function. Free Radic Biol Med. 2022;182:206-218. doi:1016/j.freeradbiomed.2022.02.021
33.  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:1016/j.diabres.2019.107801
34.  Lim AY, Chen YC, Hsu CC, Fu TC, Wang JS. The effects of exercise training on mitochondrial function in cardiovascular diseases: a systematic review and meta-analysis. Int J Mol Sci. 2022;23(20):12559. doi:3390/ijms232012559
35.  Lippi L, de Sire A, Mezian K, et al. Impact of exercise training on muscle mitochondria modifications in older adults: a systematic review of randomized controlled trials. Aging Clin Exp Res. 2022;34(7):1495-1510. doi:1007/s40520-021-02073-w
36.  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:1186/s12967-021-02737-1